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Sinberger LA, Zahavi T, Keren-Khadmy N, Dugach Y, Sonnenblick A, Salmon-Divon M. Refining prognostic tools for luminal breast cancer: genetic insights and comprehensive analysis. ESMO Open 2025; 10:105080. [PMID: 40305907 PMCID: PMC12088756 DOI: 10.1016/j.esmoop.2025.105080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 03/30/2025] [Accepted: 04/03/2025] [Indexed: 05/02/2025] Open
Abstract
BACKGROUND Luminal breast cancer (BC) is generally associated with a lower risk of recurrence compared with other subtypes. However, patients with luminal BC can still experience recurrence, which remains a significant concern and contributes to BC-related mortality. Current clinical practice for recurrence risk prognosis relies on prognostic tests based on tumor gene expression profiles. MATERIALS AND METHODS In this study, we aimed to investigate the association between different genetic alterations with the likelihood of recurrence and gene expression prognostic prediction (Oncotype DX®, MammaPrint®, and PAM50-ROR) in luminal BC patients. We constructed three transcriptome-based predictive models, based on these widely used clinical tests, to evaluate the recurrence risk of patients with luminal BC, using RNA-seq data from 1527 samples across 11 datasets. We further classified 1780 patients from the TCGA and METABRIC datasets into risk groups and detected distinct recurrence risk patterns. RESULTS Our analysis revealed that low-risk groups had higher frequencies of mutations in PIK3CA, MAP3K1, CDH1, KMT2C, and CBFB, as well as co-mutations in PIK3CA-MAP3K1, PIK3CA-CBFB, and KMT2C-MAP3K1. In contrast, high-risk groups showed enrichment of TP53, RB1, and PTPN22 mutations compared with the whole cohort, with notable co-mutations in TP53-PIK3CA and TP53-KMT2C. Furthermore, mutations in TP53 and BRCA2, and deletions in the 7p22.3 region were at least threefold more frequent in high-risk patients compared with low-risk patients. Using an independent dataset, we validated our finding of higher frequency of BRCA2 mutations in Oncotype DX® high-risk patients. Notably, PIK3CA mutations had an unexpected negative impact on recurrence and survival among high-risk patients. CONCLUSION Our study reveals key genetic factors associated with recurrence risk in luminal BC. Identifying these mutations and copy number alterations provides a basis for refined prognostic models and suggests avenues for further research, potentially improving treatment strategies and follow-up care for patients with luminal BC.
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Affiliation(s)
- L A Sinberger
- Department of Molecular Biology, Ariel University, Ariel, Israel
| | - T Zahavi
- Department of Molecular Biology, Ariel University, Ariel, Israel
| | - N Keren-Khadmy
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Y Dugach
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - A Sonnenblick
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - M Salmon-Divon
- Department of Molecular Biology, Ariel University, Ariel, Israel; Adelson School of Medicine, Ariel University, Ariel, Israel.
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Famili-Youth EHH, Famili-Youth A, Yang D, Siddique A, Wu EY, Liu W, Resnick MB, Chen Q, Brodsky AS. Aberrant expression of collagen type X in solid tumor stroma is associated with EMT, immunosuppressive and pro-metastatic pathways, bone marrow stromal cell signatures, and poor survival prognosis. BMC Cancer 2025; 25:247. [PMID: 39939916 PMCID: PMC11823173 DOI: 10.1186/s12885-025-13641-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 02/04/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Collagen type X (ColXα1, encoded by COL10A1) is expressed specifically in the cartilage-to-bone transition, in bone marrow cells, and in osteoarthritic (OA) cartilage. We have previously shown that ColXα1 is expressed in breast tumor stroma, correlates with tumor-infiltrating lymphocytes, and predicts poor adjuvant therapy outcomes in ER+/HER2+ breast cancer. However, the underlying molecular mechanisms for these effects are unknown. In this study, we performed bioinformatic analysis of COL10A1-associated gene modules in breast and pancreatic cancer as well as in cells from bone marrow and OA cartilage. These findings provide important insights into the mechanisms of transcriptional and extracellular matrix changes which impact the local stromal microenvironment and tumor progression. METHODS Immunohistochemistry was performed to examine collagen type X expression in solid tumors. WGCNA was used to generate COL10A1-associated gene networks in breast and pancreatic tumor cohorts using RNA-Seq data from The Cancer Genome Atlas. Computational analysis was employed to assess the impact of these gene networks on development and progression of cancer and OA. Data processing and statistical analysis was performed using R and various publicly-available computational tools. RESULTS Expression of COL10A1 and its associated gene networks highlights inflammatory and immunosuppressive microenvironments, which identify aggressive breast and pancreatic tumors and contribute to metastatic potential in a sex-dependent manner. Both cancer types are enriched in stroma, and COL10A1 implicates bone marrow-derived fibroblasts as contributors to the epithelial-to-mesenchymal transition (EMT) in these tumors. Heightened expression of COL10A1 and its associated gene networks is correlated with poorer patient outcomes in both breast and pancreatic cancer. Common transcriptional changes and chondrogenic activity are shared between cancer and OA cartilage, suggesting that similar microenvironmental alterations may underlie both diseases. CONCLUSIONS COL10A1-associated gene networks may hold substantial value as regulators and biomarkers of aggressive tumor phenotypes with implications for therapy development and clinical outcomes. Identification of tumors which exhibit high expression of COL10A1 and its associated genes may reveal the presence of bone marrow-derived stromal microenvironments with heightened EMT capacity and metastatic potential. Our analysis may enable more effective risk assessment and more precise treatment of patients with breast and pancreatic cancer.
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Affiliation(s)
- Elliot H H Famili-Youth
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA.
| | - Aryana Famili-Youth
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA.
| | - Dongfang Yang
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Ayesha Siddique
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Elizabeth Y Wu
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Wenguang Liu
- Department of Orthopedics, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
- Present address: School of Food Science and Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, Shaanxi, China
| | - Murray B Resnick
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Qian Chen
- Department of Orthopedics, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.
| | - Alexander S Brodsky
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
- Center for Computational Molecular Biology, Brown University, Providence, RI, USA
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Mohseninia N, Eisazadeh R, Mirshahvalad SA, Zamani-Siahkali N, Hörmann AA, Pirich C, Iagaru A, Beheshti M. Diagnostic Value of Gastrin-Releasing Peptide Receptor-Targeted PET Imaging in Oncology: A Systematic Review. Semin Nucl Med 2025:S0001-2998(25)00001-7. [PMID: 39855939 DOI: 10.1053/j.semnuclmed.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 12/25/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025]
Abstract
Gastrin-releasing peptide receptor (GRPR), overexpressed in various cancers, is a promising target for positron emission tomography (PET). This systematic review investigated the diagnostic value of GRPR-targeted PET imaging in oncology. A systematic search was conducted on major medical databases until May 23, 2024. Keywords were modified to include clinical original studies on GRPR-targeted PET in cancer patients. Out of 1624 searched studies initially, 107 were eligible for the full-text review. Overall, data from 38 studies met inclusion criteria, investigating GRPR-targeting radiotracers in breast cancer, prostate cancer, gastrointestinal stromal tumours (GIST) and gliomas (including optic pathway glioma and glioblastoma multiforme). In breast cancer, GRPR-targeted PET effectively detected primary tumours and metastases, particularly in estrogen receptor (ER)-positive patients, and predicted treatment response. In prostate cancer, high sensitivity (up to 88%) and specificity (up to 90%) for detecting primary tumours were observed, providing added value when combined with magnetic resonance imaging (MRI). In biochemical recurrence, sites of prostate cancer were identified even at PSA levels below 0.5ng/dL. Compared with PSMA PET, GRPR-targeted PET showed comparable or superior detection rates. Considering GIST, GRPR-targeted PET imaging proved to be a valuable diagnostic tool, particularly when [18F] FDG PET results were inconclusive. Regarding gliomas, GRPR-targeted PET achieved a 100% detection rate (MRI reference), aiding localization, preoperative planning, and differentiation between recurrence and malignant transformation. GRPR-targeted PET shows promise in improving cancer diagnostics, particularly in ER-positive breast cancer, prostate cancer, and gliomas, and may enhance clinical decision-making.
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Affiliation(s)
- Nasibeh Mohseninia
- Division of Molecular Imaging and Theranostics, Department of Nuclear Medicine, University Hospital, Paracelsus Medical University, Salzburg, Austria
| | - Roya Eisazadeh
- Division of Molecular Imaging and Theranostics, Department of Nuclear Medicine, University Hospital, Paracelsus Medical University, Salzburg, Austria
| | - Seyed Ali Mirshahvalad
- Division of Molecular Imaging and Theranostics, Department of Nuclear Medicine, University Hospital, Paracelsus Medical University, Salzburg, Austria; Joint Department of Medical Imaging, University Medical Imaging Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Nazanin Zamani-Siahkali
- Division of Molecular Imaging and Theranostics, Department of Nuclear Medicine, University Hospital, Paracelsus Medical University, Salzburg, Austria; Department of Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Anton Amadeus Hörmann
- Division of Molecular Imaging and Theranostics, Department of Nuclear Medicine, University Hospital, Paracelsus Medical University, Salzburg, Austria
| | - Christian Pirich
- Division of Molecular Imaging and Theranostics, Department of Nuclear Medicine, University Hospital, Paracelsus Medical University, Salzburg, Austria
| | - Andrei Iagaru
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, Stanford, CA
| | - Mohsen Beheshti
- Division of Molecular Imaging and Theranostics, Department of Nuclear Medicine, University Hospital, Paracelsus Medical University, Salzburg, Austria.
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Famili-Youth EHH, Famili-Youth A, Yang D, Siddique A, Wu EY, Liu W, Resnick MB, Chen Q, Brodsky AS. Aberrant expression of collagen type X in solid tumor stroma is associated with EMT, immunosuppressive and pro-metastatic pathways, bone marrow stromal cell signatures, and poor survival prognosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.13.621984. [PMID: 39605631 PMCID: PMC11601388 DOI: 10.1101/2024.11.13.621984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Background Collagen type X (ColXα1, encoded by COL10A1) is expressed specifically in the cartilage-to-bone transition, in bone marrow cells, and in osteoarthritic (OA) cartilage. We have previously shown that ColXα1 is expressed in breast tumor stroma, correlates with tumor-infiltrating lymphocytes, and predicts poor adjuvant therapy outcomes in ER+/HER2+ breast cancer. However, the underlying molecular mechanisms for these effects are unknown. In this study, we performed bioinformatic analysis of COL10A1-associated gene modules in breast and pancreatic cancer as well as in cells from bone marrow and OA cartilage. These findings provide important insights into the mechanisms of transcriptional and extracellular matrix changes which impact the local stromal microenvironment and tumor progression. Methods Immunohistochemistry was performed to examine collagen type X expression in solid tumors. WGCNA was used to generate COL10A1-associated gene networks in breast and pancreatic tumor cohorts using RNA-Seq data from The Cancer Genome Atlas. Computational analysis was employed to assess the impact of these gene networks on development and progression of cancer and OA. Data processing and statistical analysis was performed using R and various publicly-available computational tools. Results Expression of COL10A1 and its associated gene networks highlights inflammatory and immunosuppressive microenvironments, which identify aggressive breast and pancreatic tumors and contribute to metastatic potential in a sex-dependent manner. Both cancer types are enriched in stroma, and COL10A1 implicates bone marrow-derived fibroblasts as drivers of the epithelial-to-mesenchymal transition (EMT) in these tumors. Heightened expression of COL10A1 and its associated gene networks is correlated with poorer patient outcomes in both breast and pancreatic cancer. Common transcriptional changes and chondrogenic activity are shared between cancer and OA cartilage, suggesting that similar microenvironmental alterations may underlie both diseases. Conclusions COL10A1-associated gene networks may hold substantial value as regulators and biomarkers of aggressive tumor phenotypes with implications for therapy development and clinical outcomes. Identification of tumors which exhibit high expression of COL10A1 and its associated genes may reveal the presence of bone marrow-derived stromal microenvironments with heightened EMT capacity and metastatic potential. Our analysis may enable more effective risk assessment and more precise treatment of patients with breast and pancreatic cancer.
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Affiliation(s)
- Elliot H H Famili-Youth
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Aryana Famili-Youth
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Dongfang Yang
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Ayesha Siddique
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Elizabeth Y Wu
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Wenguang Liu
- Department of Orthopedics, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Murray B Resnick
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Qian Chen
- Department of Orthopedics, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Alexander S Brodsky
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA
- Center for Computational Molecular Biology, Brown University, Providence, RI, USA
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Müller C, Oliveira-Ferrer L, Müller V, Schmalfeldt B, Windhorst S. Transcriptome-based identification of key actin-binding proteins associated with high metastatic potential in breast cancer. Front Mol Biosci 2024; 11:1440276. [PMID: 39281318 PMCID: PMC11392851 DOI: 10.3389/fmolb.2024.1440276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/05/2024] [Indexed: 09/18/2024] Open
Abstract
Introduction Actin-binding proteins (ABPs) are essential for the regulation of morphological plasticity required for tumor cells to metastasize. The aim of this study was to perform an unbiased bioinformatic approach to identify the key ABPs significantly associated with the metastatic potential of breast cancer cells. Methods Microarray data from 181 primary breast cancer samples from our hospital were used, and all genes belonging to the Gene Ontology term actin cytoskeleton organization were obtained from QuickGO. Association with metastasis-free survival probability was tested using Cox proportional hazards regression, and pairwise co-expression was tested by Pearson correlations. Differential expression between different subgroups was analyzed using Wilcoxon tests for dichotomous traits and Kruskal-Wallis tests for categorical traits. Validation was performed using four publicly available breast cancer datasets. Results ARHGAP25 was significantly associated with a low metastatic potential, and CFL1, TMSB15A, and ACTL8 were significantly associated with a high metastatic potential. A significantly higher expression of CFL1, TMSB15A, and ACTL8 mRNA was found in the more aggressive Her2-positive and triple-negative subtypes as well as in ER-negative samples. Also, these genes were co-expressed in the same tumors. However, only mRNA levels of CFL1 were increased in pN1 compared to pN0 patients. External validation revealed that CFL1 and TMSB15A had significant associations with consistent hazard ratios in two breast cancer cohorts, and among these, CFL1 exhibited the highest hazard ratios. Conclusion CFL1 showed the strongest correlation with the metastatic potential of breast tumors. Thus, targeted inhibition of CFL1 might be a promising approach to treat malignant breast cancer cells.
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Affiliation(s)
- Christian Müller
- Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Volkmar Müller
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Barbara Schmalfeldt
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Windhorst
- Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Bottosso M, Miglietta F, Vernaci GM, Giarratano T, Dieci MV, Guarneri V, Griguolo G. Gene Expression Assays to Tailor Adjuvant Endocrine Therapy for HR+/HER2- Breast Cancer. Clin Cancer Res 2024; 30:2884-2894. [PMID: 38656833 PMCID: PMC11247313 DOI: 10.1158/1078-0432.ccr-23-4020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/11/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024]
Abstract
Adjuvant endocrine therapy (ET) represents the standard of care for almost all hormone receptor (HR)+/HER2- breast cancers, and different agents and durations are currently available. In this context, the tailoring and optimization of adjuvant endocrine treatment by reducing unnecessary toxic treatment while taking into account the biological heterogeneity of HR+/HER2- breast cancer represents a clinical priority. There is therefore a significant need for the integration of biological biomarkers in the choice of adjuvant ET beyond currently used clinicopathological characteristics. Several gene expression assays have been developed to identify patients with HR+/HER2- breast cancer who will not derive benefit from the addition of adjuvant chemotherapy. By enhancing risk stratification and predicting therapeutic response, genomic assays have also shown to be a promising tool for optimizing endocrine treatment decisions. In this study, we review evidence supporting the use of most common commercially available gene expression assays [Oncotype DX, MammaPrint, Breast Cancer Index (BCI), Prosigna, and EndoPredict] in tailoring adjuvant ET. Available data on the use of genomic tests to inform extended adjuvant treatment choice based on the risk of late relapse and on the estimated benefit of a prolonged ET are discussed. Moreover, preliminary evidence regarding the use of genomic assays to inform de-escalation of endocrine treatment, such as shorter durations or omission, for low-risk patients is reviewed. Overall, gene expression assays are emerging as potential tools to further personalize adjuvant treatment for patients with HR+/HER2- breast cancers.
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Affiliation(s)
- Michele Bottosso
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Federica Miglietta
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | | | | | - Maria Vittoria Dieci
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Valentina Guarneri
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Gaia Griguolo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
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Wang Y, Sun W, Karlsson E, Kang Lövgren S, Ács B, Rantalainen M, Robertson S, Hartman J. Clinical evaluation of deep learning-based risk profiling in breast cancer histopathology and comparison to an established multigene assay. Breast Cancer Res Treat 2024; 206:163-175. [PMID: 38592541 PMCID: PMC11182789 DOI: 10.1007/s10549-024-07303-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 02/26/2024] [Indexed: 04/10/2024]
Abstract
PURPOSE To evaluate the Stratipath Breast tool for image-based risk profiling and compare it with an established prognostic multigene assay for risk profiling in a real-world case series of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative early breast cancer patients categorized as intermediate risk based on classic clinicopathological variables and eligible for chemotherapy. METHODS In a case series comprising 234 invasive ER-positive/HER2-negative tumors, clinicopathological data including Prosigna results and corresponding HE-stained tissue slides were retrieved. The digitized HE slides were analysed by Stratipath Breast. RESULTS Our findings showed that the Stratipath Breast analysis identified 49.6% of the clinically intermediate tumors as low risk and 50.4% as high risk. The Prosigna assay classified 32.5%, 47.0% and 20.5% tumors as low, intermediate and high risk, respectively. Among Prosigna intermediate-risk tumors, 47.3% were stratified as Stratipath low risk and 52.7% as high risk. In addition, 89.7% of Stratipath low-risk cases were classified as Prosigna low/intermediate risk. The overall agreement between the two tests for low-risk and high-risk groups (N = 124) was 71.0%, with a Cohen's kappa of 0.42. For both risk profiling tests, grade and Ki67 differed significantly between risk groups. CONCLUSION The results from this clinical evaluation of image-based risk stratification shows a considerable agreement to an established gene expression assay in routine breast pathology.
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Affiliation(s)
- Yinxi Wang
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Stratipath AB, Nanna Svartz väg 4, Stockholm, 171 65, Sweden
| | - Wenwen Sun
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
| | - Emelie Karlsson
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Sandy Kang Lövgren
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Stratipath AB, Nanna Svartz väg 4, Stockholm, 171 65, Sweden
| | - Balázs Ács
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
| | - Mattias Rantalainen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- MedTechLabs, BioClinicum, Karolinska University Hospital, Stockholm, Sweden
| | - Stephanie Robertson
- Stratipath AB, Nanna Svartz väg 4, Stockholm, 171 65, Sweden.
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
| | - Johan Hartman
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
- MedTechLabs, BioClinicum, Karolinska University Hospital, Stockholm, Sweden
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Saatci O, Alam R, Huynh-Dam KT, Isik A, Uner M, Belder N, Ersan PG, Tokat UM, Ulukan B, Cetin M, Calisir K, Gedik ME, Bal H, Sener Sahin O, Riazalhosseini Y, Thieffry D, Gautheret D, Ogretmen B, Aksoy S, Uner A, Akyol A, Sahin O. Targeting LINC00152 activates cAMP/Ca 2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer. Cell Death Dis 2024; 15:418. [PMID: 38879508 PMCID: PMC11180193 DOI: 10.1038/s41419-024-06814-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 06/05/2024] [Accepted: 06/06/2024] [Indexed: 06/19/2024]
Abstract
Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca2+ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca2+ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.
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Affiliation(s)
- Ozge Saatci
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA
| | - Rashedul Alam
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Kim-Tuyen Huynh-Dam
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA
| | - Aynur Isik
- Department of Pathology, Faculty of Medicine, Hacettepe University, 06100, Ankara, Turkey
| | - Meral Uner
- Department of Pathology, Faculty of Medicine, Hacettepe University, 06100, Ankara, Turkey
| | - Nevin Belder
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, Turkey
| | - Pelin Gulizar Ersan
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, Turkey
| | - Unal Metin Tokat
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, Turkey
| | - Burge Ulukan
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Metin Cetin
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA
| | - Kubra Calisir
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Mustafa Emre Gedik
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Hilal Bal
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, Turkey
| | - Ozlem Sener Sahin
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Yasser Riazalhosseini
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Victor Philip Dahdaleh Institute of Genomic Medicine at McGill University, Montreal, Quebec, Canada
| | - Denis Thieffry
- Département de biologie de l'Ecole normale supérieure, PSL Université, 75005, Paris, France
- Bioinformatics and Computational Systems Biology of Cancer, U900 Institut Curie - INSERM - Mines ParisTech, PSL Université, 75005, Paris, France
| | - Daniel Gautheret
- Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, CNRS, CEA, 91190, Gif-sur-Yvette, France
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Sercan Aksoy
- Department of Medical Oncology, Hacettepe University Cancer Institute, 06100, Ankara, Turkey
| | - Aysegul Uner
- Department of Pathology, Faculty of Medicine, Hacettepe University, 06100, Ankara, Turkey
| | - Aytekin Akyol
- Department of Pathology, Faculty of Medicine, Hacettepe University, 06100, Ankara, Turkey
| | - Ozgur Sahin
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA.
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9
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Zhang Y, Chen F, Balic M, Creighton CJ. An essential gene signature of breast cancer metastasis reveals targetable pathways. Breast Cancer Res 2024; 26:98. [PMID: 38867323 PMCID: PMC11167932 DOI: 10.1186/s13058-024-01855-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/04/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND The differential gene expression profile of metastatic versus primary breast tumors represents an avenue for discovering new or underappreciated pathways underscoring processes of metastasis. However, as tumor biopsy samples are a mixture of cancer and non-cancer cells, most differentially expressed genes in metastases would represent confounders involving sample biopsy site rather than cancer cell biology. METHODS By paired analysis, we defined a top set of differentially expressed genes in breast cancer metastasis versus primary tumors using an RNA-sequencing dataset of 152 patients from The Breast International Group Aiming to Understand the Molecular Aberrations dataset (BIG-AURORA). To filter the genes higher in metastasis for genes essential for breast cancer proliferation, we incorporated CRISPR-based data from breast cancer cell lines. RESULTS A significant fraction of genes with higher expression in metastasis versus paired primary were essential by CRISPR. These 264 genes represented an essential signature of breast cancer metastasis. In contrast, nonessential metastasis genes largely involved tumor biopsy site. The essential signature predicted breast cancer patient outcome based on primary tumor expression patterns. Pathways underlying the essential signature included proteasome degradation, the electron transport chain, oxidative phosphorylation, and cancer metabolic reprogramming. Transcription factors MYC, MAX, HDAC3, and HCFC1 each bound significant fractions of essential genes. CONCLUSIONS Associations involving the essential gene signature of breast cancer metastasis indicate true biological changes intrinsic to cancer cells, with important implications for applying existing therapies or developing alternate therapeutic approaches.
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Affiliation(s)
- Yiqun Zhang
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, One Baylor Plaza, MS305, Houston, TX, 77030, USA
| | - Fengju Chen
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, One Baylor Plaza, MS305, Houston, TX, 77030, USA
| | - Marija Balic
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Unit for Translational Breast Cancer Research, Medical University of Graz, Graz, Austria
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chad J Creighton
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, One Baylor Plaza, MS305, Houston, TX, 77030, USA.
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
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10
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Wang S, Lee D. Community cohesion looseness in gene networks reveals individualized drug targets and resistance. Brief Bioinform 2024; 25:bbae175. [PMID: 38622359 PMCID: PMC11018546 DOI: 10.1093/bib/bbae175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/19/2024] [Accepted: 04/02/2024] [Indexed: 04/17/2024] Open
Abstract
Community cohesion plays a critical role in the determination of an individual's health in social science. Intriguingly, a community structure of gene networks indicates that the concept of community cohesion could be applied between the genes as well to overcome the limitations of single gene-based biomarkers for precision oncology. Here, we develop community cohesion scores which precisely quantify the community ability to retain the interactions between the genes and their cellular functions in each individualized gene network. Using breast cancer as a proof-of-concept study, we measure the community cohesion score profiles of 950 case samples and predict the individualized therapeutic targets in 2-fold. First, we prioritize them by finding druggable genes present in the community with the most and relatively decreased scores in each individual. Then, we pinpoint more individualized therapeutic targets by discovering the genes which greatly contribute to the community cohesion looseness in each individualized gene network. Compared with the previous approaches, the community cohesion scores show at least four times higher performance in predicting effective individualized chemotherapy targets based on drug sensitivity data. Furthermore, the community cohesion scores successfully discover the known breast cancer subtypes and we suggest new targeted therapy targets for triple negative breast cancer (e.g. KIT and GABRP). Lastly, we demonstrate that the community cohesion scores can predict tamoxifen responses in ER+ breast cancer and suggest potential combination therapies (e.g. NAMPT and RXRA inhibitors) to reduce endocrine therapy resistance based on individualized characteristics. Our method opens new perspectives for the biomarker development in precision oncology.
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Affiliation(s)
- Seunghyun Wang
- Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea
| | - Doheon Lee
- Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea
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11
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Chua BH. Omission of radiation therapy post breast conserving surgery. Breast 2024; 73:103670. [PMID: 38211516 PMCID: PMC10788792 DOI: 10.1016/j.breast.2024.103670] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 12/24/2023] [Accepted: 01/04/2024] [Indexed: 01/13/2024] Open
Abstract
Radiation therapy (RT) after breast conserving surgery decreases the risks of local recurrence and breast cancer mortality in the multidisciplinary management of patients with breast cancer. However, breast cancer is a heterogeneous disease, and the absolute benefit of post-operative RT in individual patients varies substantially. Clinical trials aiming to identify patients with low-risk early breast cancer in whom post-operative RT may be safely omitted, based on conventional clinical-pathologic variables alone, have not provided sufficiently tailored information on local recurrence risk assessment to guide treatment decisions. The majority of patients with early breast cancer continue to be routinely treated with RT after breast conserving surgery. This approach may represent over-treatment for a substantial proportion of the patients. The clinical impact of genomic signatures on local therapy decisions for early breast cancer has been remarkably modest due to the lack of high-level evidence supporting their clinical validity for assessment of the risk of local recurrence. Efforts to personalise breast cancer care must be supported by high level evidence to enable balanced, informed treatment decisions. These considerations underpin the importance of ongoing biomarker-directed clinical trials to generate the high-level evidence necessary for setting the future standard of care in personalised local therapy for patients with early breast cancer.
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Affiliation(s)
- Boon H Chua
- Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia.
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12
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Wang J, Chen H, Koenig J, Wu Y, Bedrosian I, Arun B, Ding Q, Khazai L, Resetkova E, Huo L, Sneige N, Albarracin C. Discordance of Oncotype DX scores in synchronous bilateral and unilateral multifocal breast cancers. Breast Cancer Res Treat 2024; 203:73-83. [PMID: 37751078 DOI: 10.1007/s10549-023-07119-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/25/2023] [Indexed: 09/27/2023]
Abstract
PURPOSE Oncotype DX, a 21-gene expression profiling test, has become standard of care in the management of estrogen receptor (ER)-positive breast cancer. In multifocal tumors, it is unclear whether testing of the different foci is necessary. We evaluated the concordance of Oncotype DX recurrence scores (RS) between 2 tumor foci in synchronous bilateral or unilateral multifocal tumors and characterized pathological predictors of discordance. METHODS We reviewed 713 ER+, HER2- primary invasive breast cancer patients with Oncotype RS and identified 17 bilateral synchronous patients (34 tumors) and 13 unilateral multifocal patients (26 tumors) with available Oncotype RS on all foci. Discordance in Oncotype RS between synchronous tumors was recorded and associations with clinicopathologic features including tumor size, histology, Nottingham histologic grade, progesterone receptor staining, and Ki67 index were analyzed. RESULTS Bilateral synchronous tumors were present in older patients (median age 59 years) and had larger tumor (median size 17 mm) and more discordant histology (10/17, 59%) as compared to unilateral multifocal tumors (median age 49 years, p < 0.01; median tumor size 12 mm, p = 0.01; discordant histology 2/13, 15%, p = 0.03). Oncotype RS were discordant in 47% (8/17) of bilateral and 54% (7/13) of unilateral multifocal tumors. Concordant Oncotype RS was associated with similar histologic grade and Ki67 index in 78% (7/9) of bilateral and 100% (6/6) of multifocal tumors. In contrast, only 25% (2/8) of bilateral (p = 0.06) and 14% (1/7) of unilateral multifocal (p < 0.01) cases with discordant Oncotype RS had concordant histology grades and Ki67 levels. In synchronous tumors with discordant Oncotype RS and Ki67 index, all (4/4) foci with higher RS had higher Ki67 index. CONCLUSION Discordance of Oncotype RS is common in both bilateral and unilateral multifocal breast cancer and is likely associated with discordant histologic grade or Ki67.
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Affiliation(s)
- Jing Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hui Chen
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 085, G1.3617B, Houston, TX, 77030, USA.
| | - Jenna Koenig
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yun Wu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Isabelle Bedrosian
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Banu Arun
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qingqing Ding
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Laila Khazai
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Erika Resetkova
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lei Huo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nour Sneige
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Constance Albarracin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 085, G1.3617A, Houston, TX, 77030, USA.
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13
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Saatci O, Alam R, Huynh-Dam KT, Isik A, Uner M, Belder N, Ersan PG, Cetin M, Tokat UM, Gedik ME, Bal H, Sahin OS, Riazalhosseini Y, Thieffry D, Gautheret D, Ogretmen B, Aksoy S, Uner A, Akyol A, Sahin O. Targeting LINC00152 activates cAMP/Ca 2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.05.565697. [PMID: 38496603 PMCID: PMC10942410 DOI: 10.1101/2023.11.05.565697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER+) breast cancer, constituting around 75% of all cases. However, emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance via blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of cAMP/PKA/CREB axis and increased expression of TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels. These ultimately induce lipid peroxidation and ferroptotic cell death in combination with tamoxifen. Overexpressing PDE4D rescues LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of ferroptosis induction and tamoxifen sensitization, thereby revealing LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.
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Affiliation(s)
- Ozge Saatci
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA
| | - Rashed Alam
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Kim-Tuyen Huynh-Dam
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA
| | - Aynur Isik
- Department of Pathology, Faculty of Medicine, Hacettepe University, 06100, Ankara, TURKEY
| | - Meral Uner
- Department of Pathology, Faculty of Medicine, Hacettepe University, 06100, Ankara, TURKEY
| | - Nevin Belder
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, TURKEY
| | - Pelin Gulizar Ersan
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, TURKEY
| | - Metin Cetin
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA
| | - Unal Metin Tokat
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, TURKEY
| | - Mustafa Emre Gedik
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Hilal Bal
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, 06800, TURKEY
| | - Ozlem Sener Sahin
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Yasser Riazalhosseini
- Department of Human Genetics, McGill University, Montreal, Quebec, CANADA
- Victor Philip Dahdaleh Institute of Genomic Medicine at McGill University, Montreal, Quebec, CANADA
| | - Denis Thieffry
- Département de biologie de l'Ecole normale supérieure, PSL Université, 75005 Paris, FRANCE
| | - Daniel Gautheret
- Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, CNRS, CEA, 91190, Gifsur-Yvette, FRANCE
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Sercan Aksoy
- Department of Medical Oncology, Hacettepe University Cancer Institute, 06100, Ankara, TURKEY
| | - Aysegul Uner
- Department of Pathology, Faculty of Medicine, Hacettepe University, 06100, Ankara, TURKEY
| | - Aytekin Akyol
- Department of Pathology, Faculty of Medicine, Hacettepe University, 06100, Ankara, TURKEY
| | - Ozgur Sahin
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA
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14
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Matheka M, Mutebi M, Sayed S, Shah J, Shaikh AJ. Metastatic breast cancer in Kenya: survival, prognosis and management at a tertiary referral centre. Ecancermedicalscience 2023; 17:1566. [PMID: 37396100 PMCID: PMC10310329 DOI: 10.3332/ecancer.2023.1566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Indexed: 07/04/2023] Open
Abstract
There has been an increase in breast cancer in Africa with up to 77% of patients diagnosed with advanced disease. However, there is little data on survival outcomes and prognostic factors affecting survival in patients with metastatic breast cancer (MBC) in Africa. The study objective was to establish the survival of patients with MBC at a single tertiary health facility, the clinical and pathological characteristics affecting survival and describe the treatment modalities used. This was a retrospective descriptive study conducted at Aga Khan University Hospital, Nairobi of patients diagnosed with MBC between 2009 and 2017. Survival data was collected on metastatic free survival, survival time between diagnosis of first metastasis and death and overall survival. Data on patient's age, menopausal status and stage at diagnosis, tumour grade, receptor status, site of metastasis and treatment given was also collected. The Kaplan-Meier Estimator was used to estimate survival. Prognostic factors for survival outcomes were analysed using univariate analysis. Standard descriptive statistics were used to describe patient characteristics. A total of 131 patients were included in the study. The median survival was 22 months. The 3 and 5-year survivals were 31.3% and 10.7%, respectively. On univariate analysis, the Luminal A molecular subtype was a significant positive prognostic factor hazard ratios (HR 0.652 95% confidence interval (CI) 0.473-0.899) while metastasis to the liver or brain were significant negative prognostic factors (HR 0.615 95% CI 0.413-0.915 and HR 0.566 95% CI 0.330-0.973, respectively). A large proportion (87.0%) received some treatment for metastatic disease. Our study concluded that survival rates for patients diagnosed with MBC were lower compared to studies from Western countries but higher than in studies from Sub-Saharan Africa. Luminal A molecular subtype was found to be a positive prognostic factor and metastasis to the liver or brain were found to be negative prognostic factors. Improved access to adequate treatment for MBC is required in the region.
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Affiliation(s)
- Mwongeli Matheka
- Aga Khan University Hospital Nairobi, PO Box 30270 - 00100, Nairobi, Kenya
| | - Miriam Mutebi
- Aga Khan University Hospital Nairobi, PO Box 30270 - 00100, Nairobi, Kenya
| | - Shahin Sayed
- Aga Khan University Hospital Nairobi, PO Box 30270 - 00100, Nairobi, Kenya
| | - Jasmit Shah
- Department of Medicine, Aga Khan University, PO Box 30270 - 00100, Nairobi, Kenya
- Brain and Mind Institute, Aga Khan University, PO Box 30270 - 00100, Nairobi, Kenya
| | - Asim Jamal Shaikh
- Sultan Qaboos Comprehensive Cancer Care and Research Centre, Muscat, Oman
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15
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Maghsoudi M, Aghdam R, Eslahchi C. Removing the association of random gene sets and survival time in cancers with positive random bias using fixed-point gene set. Sci Rep 2023; 13:8663. [PMID: 37248269 DOI: 10.1038/s41598-023-35588-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 05/20/2023] [Indexed: 05/31/2023] Open
Abstract
Cancer research aims to identify genes that cause or control disease progression. Although a wide range of gene sets have been published, they are usually in poor agreement with one another. Furthermore, recent findings from a gene-expression cohort of different cancer types, known as positive random bias, showed that sets of genes chosen randomly are significantly associated with survival time much higher than expected. In this study, we propose a method based on Brouwer's fixed-point theorem that employs significantly survival-associated random gene sets and reveals a small fixed-point gene set for cancers with a positive random bias property. These sets significantly correspond to cancer-related pathways with biological relevance for the progression and metastasis of the cancer types they represent. Our findings show that our proposed significant gene sets are biologically related to each cancer type available in the cancer genome atlas with the positive random bias property, and by using these sets, positive random bias is significantly more reduced in comparison with state-of-the-art methods in this field. The random bias property is removed in 8 of these 17 cancer types, and the number of random sets of genes associated with survival time is significantly reduced in the remaining 9 cancers.
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Affiliation(s)
- Maryam Maghsoudi
- School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
| | - Rosa Aghdam
- School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, 53715, USA
| | - Changiz Eslahchi
- School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran.
- Department of Computer and Data Sciences, Faculty of Mathematical Sciences, Shahid Beheshti University, Tehran, Iran.
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16
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Shieh Y, Roger J, Yau C, Wolf DM, Hirst GL, Swigart LB, Huntsman S, Hu D, Nierenberg JL, Middha P, Heise RS, Shi Y, Kachuri L, Zhu Q, Yao S, Ambrosone CB, Kwan ML, Caan BJ, Witte JS, Kushi LH, 't Veer LV, Esserman LJ, Ziv E. Development and testing of a polygenic risk score for breast cancer aggressiveness. NPJ Precis Oncol 2023; 7:42. [PMID: 37188791 PMCID: PMC10185660 DOI: 10.1038/s41698-023-00382-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 04/28/2023] [Indexed: 05/17/2023] Open
Abstract
Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS's association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06-1.21, p = 4.0 × 10-4). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRSER-/ER+). Furthermore, its effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention.
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Affiliation(s)
- Yiwey Shieh
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
| | - Jacquelyn Roger
- PhD Program in Biological and Medical Informatics, University of California, San Francisco, San Francisco, CA, USA
| | - Christina Yau
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Denise M Wolf
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Gillian L Hirst
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Lamorna Brown Swigart
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Scott Huntsman
- Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Donglei Hu
- Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Jovia L Nierenberg
- Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Pooja Middha
- Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Rachel S Heise
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Yushu Shi
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Linda Kachuri
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
| | - Qianqian Zhu
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Song Yao
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christine B Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Marilyn L Kwan
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Bette J Caan
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - John S Witte
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
| | - Lawrence H Kushi
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Laura van 't Veer
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Laura J Esserman
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Elad Ziv
- Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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17
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Elson NC, Lewis JD, Shaughnessy EA, Reyna C. Lessons from other fields of medicine, Part 1: Breast cancer. HANDBOOK OF CLINICAL NEUROLOGY 2023; 192:101-118. [PMID: 36796936 DOI: 10.1016/b978-0-323-85538-9.00003-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Through the understanding of multiple etiologies, pathologies, and disease progression trajectories, breast cancer shifted historically from a singular malignancy of the breast to a complex of molecular/biological entities, translating into individualized disease-modifying treatments. As a result, this led to various de-escalations of treatment compared with the gold standard in the era preceding systems biology: radical mastectomy. Targeted therapies have minimized morbidity from the treatments and mortality from the disease. Biomarkers further individualized tumor genetics and molecular biology to optimize treatments targeting specific cancer cells. Landmark discoveries in breast cancer management have evolved through histology, hormone receptors, human epidermal growth factor, single-gene prognostic markers, and multigene prognostic markers. Relevant to the reliance on histopathology in neurodegenerative disorders, histopathology evaluation in breast cancer can serve as a marker of overall prognosis rather than predict response to therapies. This chapter reviews the successes and failures of breast cancer research through history, with focus on the transition from a universal approach for all patients to divergent biomarker development and individualized targeted therapies, discussing future areas of growth in the field that may apply to neurodegenerative disorders.
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Affiliation(s)
- Nora C Elson
- Department of Surgery, Good Samaritan TriHealth Hospitals, Cincinnati, OH, United States
| | - Jaime D Lewis
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH, United States
| | - Elizabeth A Shaughnessy
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH, United States
| | - Chantal Reyna
- Department of Surgery, Crozer Health Hospitals, Springfield, PA, United States.
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18
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Li C, Li W, Zhu W. Penalized robust learning for optimal treatment regimes with heterogeneous individualized treatment effects. J Appl Stat 2023; 51:1151-1170. [PMID: 38628447 PMCID: PMC11018073 DOI: 10.1080/02664763.2023.2180167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 02/05/2023] [Indexed: 02/22/2023]
Abstract
The growing popularity of personalized medicine motivates people to explore individualized treatment regimes according to heterogeneous characteristics of the patients. For the large-scale data analysis, however, the data are collected at different times and different locations, i.e. subjects are usually from a heterogeneous population, which causes that the optimal treatment regimes also vary for patients across different subgroups. In this paper, we mainly focus on the estimation of optimal treatment regimes for subjects come from a heterogeneous population with high-dimensional data. We first remove the main effects of the covariates for each subgroup to eliminate non-ignorable residual confounding. Based on the centralized outcome, we propose a penalized robust learning that estimates the coefficient matrix of the interactions between covariates and treatment by penalizing pairwise differences of the coefficients of any two subgroups for the same covariate, which can automatically identify the latent complex structure of the coefficient matrix with heterogeneous and homogeneous columns. At the same time, the penalized robust learning can also select the important variables that truly contribute to the individualized treatment decisions with commonly used sparsity structure penalty. Extensive simulation studies show that our proposed method outperforms current popular methods, and it is further illustrated in the real analysis of the Tamoxifen breast cancer data.
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Affiliation(s)
- Canhui Li
- Key Laboratory for Applied Statistics of MOE and School of Mathematics and Statistics, Northeast Normal University, Changchun, People's Republic of China
| | - Weirong Li
- Key Laboratory for Applied Statistics of MOE and School of Mathematics and Statistics, Northeast Normal University, Changchun, People's Republic of China
| | - Wensheng Zhu
- Key Laboratory for Applied Statistics of MOE and School of Mathematics and Statistics, Northeast Normal University, Changchun, People's Republic of China
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19
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Wang J, Marion-Gallois R. Propensity score matching and stratification using multiparty data without pooling. Pharm Stat 2023; 22:4-19. [PMID: 35733398 DOI: 10.1002/pst.2250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/01/2022] [Accepted: 05/29/2022] [Indexed: 02/01/2023]
Abstract
Matching and stratification based on confounding factors or propensity scores (PS) are powerful approaches for reducing confounding bias in indirect treatment comparisons. However, implementing these approaches requires pooled individual patient data (IPD). The research presented here was motivated by an indirect comparison between a single-armed trial in acute myeloid leukemia (AML), and two external AML registries with current treatments for a control. For confidentiality reasons, IPD cannot be pooled. Common approaches to adjusting confounding bias, such as PS matching or stratification, cannot be applied as 1) a model for PS, for example, a logistic model, cannot be fitted without pooling covariate data; 2) pooling response data may be necessary for some statistical inference (e.g., estimating the SE of mean difference of matched pairs) after PS matching. We propose a set of approaches that do not require pooling IPD, using a combination of methods including a linear discriminant for matching and stratification, and secure multiparty computation for estimation of within-pair sample variance and for calculations involving multiple control sources. The approaches only need to share aggregated data offline, rather than real-time secure data transfer, as required by typical secure multiparty computation for model fitting. For survival analysis, we propose an approach using restricted mean survival time. A simulation study was conducted to evaluate this approach in several scenarios, in particular, with a mixture of continuous and binary covariates. The results confirmed the robustness and efficiency of the proposed approach. A real data example is also provided for illustration.
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20
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Patterns of immune infiltration and survival in endocrine therapy-treated ER-positive breast cancer: A computational study of 1900 patients. Biomed Pharmacother 2022; 155:113787. [DOI: 10.1016/j.biopha.2022.113787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/16/2022] [Accepted: 09/28/2022] [Indexed: 11/21/2022] Open
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Garan LAW, Xiao Y, Lin WC. 14-3-3τ drives estrogen receptor loss via ERα36 induction and GATA3 inhibition in breast cancer. Proc Natl Acad Sci U S A 2022; 119:e2209211119. [PMID: 36252018 PMCID: PMC9618134 DOI: 10.1073/pnas.2209211119] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 09/21/2022] [Indexed: 11/18/2022] Open
Abstract
About one-fourth of recurrent estrogen receptor-positive (ER+) breast cancers lose ER expression, leading to endocrine therapy failure. However, the mechanisms underlying ER loss remain to be fully explored. We now show that 14-3-3τ, up-regulated in ∼60% of breast cancer, drives the conversion of ER+ to ER- and epithelial-to-mesenchymal transition (EMT). We identify ERα36, an isoform of ERα66, as a downstream effector of 14-3-3τ. Overexpression of 14-3-3τ induces ERα36 in xenografts and tumor spheroids. The regulation is further supported by a positive correlation between ERα36 and 14-3-3τ expression in human breast cancers. ERα36 can antagonize ERα66 and inhibit ERα66 expression. Isoform-specific depletion of ERα36 blocks the ER conversion and EMT induced by 14-3-3τ overexpression in tumor spheroids, thus establishing ERα36 as a key mediator in 14-3-3τ-driven ER loss and EMT. ERα36 promoter is repressed by GATA3, which can be phosphorylated by AKT at consensus binding sites for 14-3-3. Upon AKT activation, 14-3-3τ binds phosphorylated GATA3 and facilitates the degradation of GATA3 causing GATA3 to lose transcriptional control over its target genes ERα66 and ERα36. We also demonstrate a role for the collaboration between 14-3-3τ and AKT in ERα36 induction and endocrine therapy resistance by three-dimensional spheroid and tamoxifen treatment models in MCF7 and T47D ER+ breast cancer cells. Thus, the 14-3-3τ-ERα36 regulation provides a previously unrecognized mechanism for ER loss and endocrine therapy failure.
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Affiliation(s)
- Lidija A. Wilhelms Garan
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030
- Cancer and Cell Biology Graduate Program, Baylor College of Medicine, Houston, TX 77030
| | - Yang Xiao
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030
| | - Weei-Chin Lin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030
- Cancer and Cell Biology Graduate Program, Baylor College of Medicine, Houston, TX 77030
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030
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22
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Wang S, Li H, Liu J, Zhang Q, Xu W, Xiang J, Fang L, Xu P, Li Z. Integrative analysis of m3C associated genes reveals METTL2A as a potential oncogene in breast Cancer. J Transl Med 2022; 20:476. [PMID: 36266694 PMCID: PMC9583565 DOI: 10.1186/s12967-022-03683-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 10/03/2022] [Indexed: 12/02/2022] Open
Abstract
RNA methylation modifications, especially m6A mRNA modification, are known to be extensively involved in tumor development. However, the relationship between N3-methylcytidine (m3C) related genes and tumorigenesis has rarely been studied. In this research, we found that m3C-related genes were expressed at different levels and affected patients’ prognosis across multiple cancer types from The Cancer Genome Atlas and multi-omics levels. Importantly, methyltransferase-like proteins 2A (METTL2A) had a high amplification frequency (~ 7%) in patients with breast invasive carcinoma (BRCA), and its overexpression was an independent predictor of poor overall survival. Enrichment analysis of associated genes revealed that METTL2A may activate DNA synthesis and cell proliferation pathways in BRCA cells. Through drug sensitivity analysis, Trifluridine, PD407824, and Taselisib were shown to be effective drugs for METTL2A-positive BRCA patients. Overall, our research conducts a holistic view of the expression level and prognostic signature of m3C-related genes with multiple malignancies. Importantly, METTL2A has been intensely explored as a potential oncogene in BRCA, to aid the development of potential drug agents for precision therapy in breast cancer patients.
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Affiliation(s)
- Shuai Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Huiting Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Jiheng Liu
- Department of Hematology and Oncology, First Hospital of Changsha, Changsha, Hunan, China
| | - Qianqian Zhang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Wei Xu
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Juanjuan Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Li Fang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Ping Xu
- Departments of Respiratory and Critical Care Medicine, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Zheng Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
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23
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Soni M, Saatci O, Gupta G, Patel Y, Keerthi Raja MR, Li J, Liu X, Xu P, Wang H, Fan D, Sahin O, Chen H. miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer. Int J Mol Sci 2022; 23:8086. [PMID: 35897675 PMCID: PMC9331933 DOI: 10.3390/ijms23158086] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/01/2023] Open
Abstract
Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.
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Affiliation(s)
- Mithil Soni
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Ozge Saatci
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; (O.S.); (P.X.); (O.S.)
| | - Gourab Gupta
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Yogin Patel
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Manikanda Raja Keerthi Raja
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Jie Li
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29201, USA;
| | - Xinfeng Liu
- Department of Mathematics, University of South Carolina, Columbia, SC 29201, USA;
| | - Peisheng Xu
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; (O.S.); (P.X.); (O.S.)
| | - Hongjun Wang
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA;
| | - Daping Fan
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA;
| | - Ozgur Sahin
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; (O.S.); (P.X.); (O.S.)
| | - Hexin Chen
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
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24
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Computational Screening of Anti-Cancer Drugs Identifies a New BRCA Independent Gene Expression Signature to Predict Breast Cancer Sensitivity to Cisplatin. Cancers (Basel) 2022; 14:cancers14102404. [PMID: 35626009 PMCID: PMC9139442 DOI: 10.3390/cancers14102404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Using a collection of publicly available drug screening resources, we identified different partners of genes associated with either sensitivity or resistance to 90 anti-cancer therapies. When subsequently applying these signatures to multiple datasets, we found that these predictive models could predict a large range of drug responses in patient samples. In particular, we discovered a new gene signature to identify breast cancer tumors that are likely to respond to cisplatin in the absence of BRCA1 mutations. This work constitutes an important advance to accelerate the application of platinum-based therapies in patient groups that are not routinely treated with these drugs. In the future, this approach may help to guide the choice of drugs based on the molecular profile of the tumors. Abstract The development of therapies that target specific disease subtypes has dramatically improved outcomes for patients with breast cancer. However, survival gains have not been uniform across patients, even within a given molecular subtype. Large collections of publicly available drug screening data matched with transcriptomic measurements have facilitated the development of computational models that predict response to therapy. Here, we generated a series of predictive gene signatures to estimate the sensitivity of breast cancer samples to 90 drugs, comprising FDA-approved drugs or compounds in early development. To achieve this, we used a cell line-based drug screen with matched transcriptomic data to derive in silico models that we validated in large independent datasets obtained from cell lines and patient-derived xenograft (PDX) models. Robust computational signatures were obtained for 28 drugs and used to predict drug efficacy in a set of PDX models. We found that our signature for cisplatin can be used to identify tumors that are likely to respond to this drug, even in absence of the BRCA-1 mutation routinely used to select patients for platinum-based therapies. This clinically relevant observation was confirmed in multiple PDXs. Our study foreshadows an effective delivery approach for precision medicine.
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25
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Choi S, Choi T, Lee HY, Han SW, Bandyopadhyay D. Doubly-robust methods for differences in restricted mean lifetimes using pseudo-observations. Pharm Stat 2022; 21:1185-1198. [PMID: 35524651 DOI: 10.1002/pst.2223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/13/2022] [Accepted: 04/20/2022] [Indexed: 11/07/2022]
Abstract
In clinical studies or trials comparing survival times between two treatment groups, the restricted mean lifetime (RML), defined as the expectation of the survival from time 0 to a prespecified time-point, is often the quantity of interest that is readily interpretable to clinicians without any modeling restrictions. It is well known that if the treatments are not randomized (as in observational studies), covariate adjustment is necessary to account for treatment imbalances due to confounding factors. In this article, we propose a simple doubly-robust pseudo-value approach to effectively estimate the difference in the RML between two groups (akin to a metric for estimating average causal effects), while accounting for confounders. The proposed method combines two general approaches: (a) group-specific regression models for the time-to-event and covariate information, and (b) inverse probability of treatment assignment weights, where the RMLs are replaced by the corresponding pseudo-observations for survival outcomes, thereby mitigating the estimation complexities in presence of censoring. The proposed estimator is double-robust, in the sense that it is consistent if at least one of the two working models remains correct. In addition, we explore the potential of available machine learning algorithms in causal inference to reduce possible bias of the causal estimates in presence of a complex association between the survival outcome and covariates. We conduct extensive simulation studies to assess the finite-sample performance of the pseudo-value causal effect estimators. Furthermore, we illustrate our methodology via application to a dataset from a breast cancer cohort study. The proposed method is implementable using the R package drRML, available in GitHub.
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Affiliation(s)
- Sangbum Choi
- Department of Statistics, Korea University, Seoul, South Korea
| | - Taehwa Choi
- Department of Statistics, Korea University, Seoul, South Korea
| | - Hye-Young Lee
- Department of Statistics, Korea University, Seoul, South Korea
| | - Sung Won Han
- School of Industrial Management Engineering, Korea University, Seoul, South Korea
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26
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Zhang X, Wu Z, Ma K. SNCA correlates with immune infiltration and serves as a prognostic biomarker in lung adenocarcinoma. BMC Cancer 2022; 22:406. [PMID: 35421944 PMCID: PMC9009002 DOI: 10.1186/s12885-022-09289-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 02/11/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The SNCA gene is a critical gene in Parkinson's disease (PD) pathology. Accumulating evidence indicates that SNCA is involved in tumorigenesis; however, the role of SNCA in lung adenocarcinoma (LUAD) remains unclear. This study aimed to explore the potential value of SNCA as a prognostic and diagnostic molecular marker in LUAD. METHODS In this study, we explored the expression pattern, prognostic value, and promoter methylation status of SNCA in LUAD based on Oncomine, UALCAN, and Kaplan-Meier Plotter. Then, using TIMER, we investigated the correlation between SNCA expression and immune infiltration. And cBioPortal were used to analysis the correlation between SNCA expression and immune checkpoint. The transcriptome data of A549 cells overexpressing SNCA were used to further study the potential immune role of SNCA in LUAD. The effect of SNCA on proliferation of A549 cells were evaluated by CCK-8, EdU and colony formation. Finally, LUAD cell lines treated with 5-aza-dC were used to explore the correlation between increased promoter methylation and downregulated mRNA expression of SNCA. RESULTS In general, the expression level of SNCA in LUAD tissue was lower than that in normal tissue, and high expression of SNCA was related to better prognosis. There were significant positive correlations between SNCA expression and immune infiltrations, including CD8+ T cells, macrophages, neutrophils, dendritic cells, B cells, and CD4+ T cells, and immune checkpoints, suggesting that immune infiltration was one of the reasons for the influence of SNCA on prognosis in LUAD. The transcriptome data of A549 cells overexpressing SNCA were further used to screen the relevant immune-related genes regulated by SNCA. Enrichment analysis confirmed that SNCA participates in the PI3K-AKT signaling pathway and other key tumor signaling pathways and regulates the expression of MAPK3, SRC, PLCG1, and SHC1. Cellular proliferation assay showed that SNCA could inhabit the growth of A549 cells via inhibiting activity of PI3K/AKT/ mTOR pathway. Finally, analysis of the methylation level of SNCA promoter showed that the promoter methylation negatively correlated with mRNA level. The expression of SNCA in LUAD cell lines was significantly upregulated by treatment with 5-aza-dC. CONCLUSION High methylation of SNCA promoter in LUAD is one of the reasons for the downregulation of SNCA mRNA level. Given that SNCA could inhibit the proliferation of A549 cells and correlates with immune infiltrates, it may serve as a prognostic biomarker in LUAD.
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Affiliation(s)
- Xiuao Zhang
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, 650118 China
| | - Zhengcun Wu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, 650118 China
| | - Kaili Ma
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, 650118 China
- Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005 China
- Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Diseases, Kunming, 650118 China
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27
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Leinert E, Schwentner L, Janni W, Wöckel A, Herbert SL, Herr D, Kühn T, Flock F, Felberbaum R, Kreienberg R, Fink V, Dayan D, Ernst K, Singer S. Outcome analysis of primary breast cancer patients who declined adjuvant chemotherapy-results from the prospective multi-center BRENDA II study. Breast Cancer 2022; 29:429-436. [PMID: 35178667 PMCID: PMC9021155 DOI: 10.1007/s12282-021-01321-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 12/01/2021] [Indexed: 11/02/2022]
Abstract
BACKGROUND This study examined 5-year overall, recurrence and distant metastasis-free survival (OS, RFS, MFS) of high- and intermediate-risk breast cancer (BC) patients who declined guideline-recommended adjuvant chemotherapy (CHT). METHODS In the prospective multicenter cohort study BRENDA II, patients with primary BC were sampled over a period of four years (2009-2012). A multi-professional team (tumorboard) discussed recommendation for adjuvant CHT according to the German guideline. Potential differences in 5 year survival were analyzed using Kaplan-Meier curves and Cox regression. The hazard ratios (HR) were adjusted for age, Charlson Comorbidity Score, American Society of Anesthesiologist (ASA) physical status classification, and endocrine therapy. RESULTS A total of 759 patients were enrolled of which 688 could receive CHT according to the guidelines (n = 219 had a clear indication, in n = 304 it was possible). For 360 patients, the tumorboard advised to perform CHT, for 304 it advised against and in 24 cases, no decision was documented. Of those with a positive suggestion, 83% received CHT. Until 5 years after diagnosis, 57 patients were deceased, 41 had at least one distant metastasis and 29 a recurrence. There was no evidence for differences in OS and MFS in patients who declined CHT despite tumorboard recommendation (HR 3.5, 95% CI 0.8-15.1 for OS, HR 1.9, 95% 0.6-6.6 for MFS). Patients who received CHT had significantly better 5-year RFS compared to those who declined (HR 0.3, 95% CI 0.1-0.9, p = 0.03). There was no evidence for different survival in those who had no CHT because of comorbidity and those who declined actively, neither for OS, MFS nor RFS. CONCLUSION The prospective BRENDA II study demonstrates benefit in RFS by guideline adherence in adjuvant breast cancer treatment, indicating prospectively the value of internationally validated guidelines in breast cancer care.
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Affiliation(s)
- Elena Leinert
- Department of Gynaecology and Obstetrics, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany.
| | - Lukas Schwentner
- Department of Gynaecology and Obstetrics, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany
| | - Wolfgang Janni
- Department of Gynaecology and Obstetrics, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany
| | - Achim Wöckel
- Department of Gynaecology and Obstetrics, University of Würzburg, Würzburg, Germany
| | - Saskia-L Herbert
- Department of Gynaecology and Obstetrics, University of Würzburg, Würzburg, Germany
| | - Daniel Herr
- Department of Gynaecology and Obstetrics, University of Würzburg, Würzburg, Germany
| | - Thorsten Kühn
- Department of Gynaecology and Obstetrics, Hospital Esslingen, Esslingen, Germany
| | - Felix Flock
- Department of Gynaecology and Obstetrics, Hospital Memmingen, Memmingen, Germany
| | - Ricardo Felberbaum
- Department of Gynaecology and Obstetrics, Hospital Kempten, Kempten, Germany
| | - Rolf Kreienberg
- Department of Gynaecology and Obstetrics, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany
| | - Visnja Fink
- Department of Gynaecology and Obstetrics, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany
| | - Davut Dayan
- Department of Gynaecology and Obstetrics, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany
| | - Kristina Ernst
- Department of Gynaecology and Obstetrics, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany
| | - Susanne Singer
- Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Centre, Johannes Gutenberg University Mainz, Mainz, Germany
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Dong H, Du L, Cai S, Lin W, Chen C, Still M, Yao Z, Coppes RP, Pan Y, Zhang D, Gao S, Zhang H. Tyrosine Phosphatase PTPRO Deficiency in ERBB2-Positive Breast Cancer Contributes to Poor Prognosis and Lapatinib Resistance. Front Pharmacol 2022; 13:838171. [PMID: 35431974 PMCID: PMC9010868 DOI: 10.3389/fphar.2022.838171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 03/07/2022] [Indexed: 02/05/2023] Open
Abstract
Despite the initial benefit from treating ERBB2-positive breast cancer with tyrosine kinase inhibitor lapatinib, resistance develops inevitably. Since the expression of protein tyrosine phosphatase receptor-type O (PTPRO), a member of the R3 subfamily of receptor protein tyrosine phosphatases (PTPs), is inversely correlated with the aggressiveness of multiple malignancies, we decided to explore the correlation between PTPRO and lapatinib resistance in ERBB2-positive breast cancer. Results of immunohistochemical (IHC) staining and the correlation analysis between the expression levels of PTPRO and the clinicopathological parameters indicate that PTPRO is downregulated in cancer tissues as compared with normal tissues and negatively associated with differentiation, tumor size, tumor depth, as well as the expression of ERBB2 and Ki67. Results from Kaplan-Meier analyses indicate that lower expression of PTPRO is correlated with shorter relapse-free survival for patients with ERBB2-positive breast cancer, and multivariable Cox regression analysis found that PTPRO can potentially serve as an independent prognostic indicator for ERBB2-positive breast cancer. Results from both human breast cancer cells with PTPRO knockdown or overexpression and mouse embryonic fibroblasts (MEFs) which derived from Ptpro +/+ and Ptpro -/- mice with then stably transfected plasmid FUGW-Erbb2 consistently demonstrated the essentiality of PTPRO in the lapatinib-mediated anticancer process. Our findings suggest that PTPRO is not only able to serve as an independent prognostic indicator, but upregulating PTPRO can also reverse the lapatinib resistance of ERBB2-positive breast cancer.
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Affiliation(s)
- Hongmei Dong
- Institute of Precision Cancer Medicine and Pathology, School of Medicine, Department of General Surgery, The First Affiliated Hospital of Jinan University, Minister of Education Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China
| | - Liang Du
- Institute of Precision Cancer Medicine and Pathology, School of Medicine, Department of General Surgery, The First Affiliated Hospital of Jinan University, Minister of Education Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China
- Departments of Biomedical Sciences of Cells and Systems, Section Molecular Cell Biology and Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- Graduate School, Shantou University Medical College, Shantou, China
| | - Songwang Cai
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Wan Lin
- Cancer Research Center, Shantou University Medical College, Shantou, China
| | - Chaoying Chen
- Graduate School, Shantou University Medical College, Shantou, China
- Department of Clinical Laboratory, The First Affiliated Hospital of Hunan Traditional Chinese Medical College (Hunan Province Directly Affiliated TCM Hospital), Zhuzhou, China
| | - Matthew Still
- Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, United States
| | - Zhimeng Yao
- Institute of Precision Cancer Medicine and Pathology, School of Medicine, Department of General Surgery, The First Affiliated Hospital of Jinan University, Minister of Education Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China
| | - Robert P. Coppes
- Departments of Biomedical Sciences of Cells and Systems, Section Molecular Cell Biology and Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Yunlong Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Dianzheng Zhang
- Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, United States
| | - Shegan Gao
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital (College of Clinical Medicine) of Henan University of Science and Technology, Luoyang, China
- *Correspondence: Hao Zhang, ; Shegan Gao,
| | - Hao Zhang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Institute of Precision Cancer Medicine and Pathology, School of Medicine, Minister of Education Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China
- *Correspondence: Hao Zhang, ; Shegan Gao,
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Lipovka Y, Alday E, Hernandez J, Velazquez C. Molecular Mechanisms of Biologically Active Compounds from Propolis in Breast Cancer: State of the Art and Future Directions. FOOD REVIEWS INTERNATIONAL 2021. [DOI: 10.1080/87559129.2021.2003380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Yulia Lipovka
- Department of Chemistry-Biology, University of Sonora, Hermosillo, Mexico
| | - Efrain Alday
- Department of Chemistry-Biology, University of Sonora, Hermosillo, Mexico
| | - Javier Hernandez
- Unidad de Servicios de Apoyo en Resolución Analítica, Universidad Veracruzana, Xalapa, Mexico
| | - Carlos Velazquez
- Department of Chemistry-Biology, University of Sonora, Hermosillo, Mexico
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30
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Panja S, Rahem S, Chu CJ, Mitrofanova A. Big Data to Knowledge: Application of Machine Learning to Predictive Modeling of Therapeutic Response in Cancer. Curr Genomics 2021; 22:244-266. [PMID: 35273457 PMCID: PMC8822229 DOI: 10.2174/1389202921999201224110101] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/16/2020] [Accepted: 09/30/2020] [Indexed: 11/22/2022] Open
Abstract
Background In recent years, the availability of high throughput technologies, establishment of large molecular patient data repositories, and advancement in computing power and storage have allowed elucidation of complex mechanisms implicated in therapeutic response in cancer patients. The breadth and depth of such data, alongside experimental noise and missing values, requires a sophisticated human-machine interaction that would allow effective learning from complex data and accurate forecasting of future outcomes, ideally embedded in the core of machine learning design. Objective In this review, we will discuss machine learning techniques utilized for modeling of treatment response in cancer, including Random Forests, support vector machines, neural networks, and linear and logistic regression. We will overview their mathematical foundations and discuss their limitations and alternative approaches in light of their application to therapeutic response modeling in cancer. Conclusion We hypothesize that the increase in the number of patient profiles and potential temporal monitoring of patient data will define even more complex techniques, such as deep learning and causal analysis, as central players in therapeutic response modeling.
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Affiliation(s)
| | | | | | - Antonina Mitrofanova
- Address correspondence to this author at the Department of Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, Newark, NJ 07107, USA; E-mail:
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31
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Song J, Tang Y, Luo X, Shi X, Song F, Ran L. Pan-Cancer Analysis Reveals the Signature of TMC Family of Genes as a Promising Biomarker for Prognosis and Immunotherapeutic Response. Front Immunol 2021; 12:715508. [PMID: 34899684 PMCID: PMC8660091 DOI: 10.3389/fimmu.2021.715508] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 10/21/2021] [Indexed: 02/05/2023] Open
Abstract
Transmembrane Channel-like (TMC) genes are critical in the carcinogenesis, proliferation, and cell cycle of human cancers. However, the multi-omics features of TMCs and their role in the prognosis and immunotherapeutic response of human cancer have not been explored. We discovered that TMCs 4-8 were commonly deregulated and correlated with patient survival in a variety of cancers. For example, TMC5 and TMC8 were correlated with the relapse and overall survival rates of breast cancer and skin melanoma, respectively. These results were validated by multiple independent cohorts. TMCs were regulated by DNA methylation and somatic alterations, such as TMC5 amplification in breast cancer (523/1062, 49.2%). Six algorithms concordantly uncovered the critical role of TMCs in the tumor microenvironment, potentially regulating immune cell toxicity and lymphocytes infiltration. Moreover, TMCs 4-8 were correlated with tumor mutation burden and expression of PD-1/PD-L1/CTLA4 in 33 cancers. Thus, we established an immunotherapy response prediction (IRP) score based on the signature of TMCs 4-8. Patients with higher IRP scores showed higher immunotherapeutic responses in five cohorts of skin melanoma (area under curve [AUC] = 0.90 in the training cohort, AUCs range from 0.70 to 0.83 in the validation cohorts). Together, our study highlights the great potential of TMCs as biomarkers for prognosis and immunotherapeutic response, which can pave the way for further investigation of the tumor-infiltrating mechanisms and therapeutic potentials of TMCs in cancer.
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Affiliation(s)
- Jing Song
- Department of Bioinformatics, The Basic Medical School of Chongqing Medical University, Chongqing, China.,Molecular and Tumor Research Center, Chongqing Medical University, Chongqing, China
| | - Yongyao Tang
- Molecular and Tumor Research Center, Chongqing Medical University, Chongqing, China
| | - Xiaoyong Luo
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Xinpeng Shi
- Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
| | - Fangzhou Song
- Molecular and Tumor Research Center, Chongqing Medical University, Chongqing, China
| | - Longke Ran
- Department of Bioinformatics, The Basic Medical School of Chongqing Medical University, Chongqing, China.,Forensic Laboratory, The Basic Medical School of Chongqing Medical University, Chongqing, China
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32
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Mammary collagen is under reproductive control with implications for breast cancer. Matrix Biol 2021; 105:104-126. [PMID: 34839002 DOI: 10.1016/j.matbio.2021.10.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 07/26/2021] [Accepted: 10/29/2021] [Indexed: 12/20/2022]
Abstract
Mammographically-detected breast density impacts breast cancer risk and progression, and fibrillar collagen is a key component of breast density. However, physiologic factors influencing collagen production in the breast are poorly understood. In female rats, we analyzed gene expression of the most abundantly expressed mammary collagens and collagen-associated proteins across a pregnancy, lactation, and weaning cycle. We identified a triphasic pattern of collagen gene regulation and evidence for reproductive state-dependent composition. An initial phase of collagen deposition occurred during pregnancy, followed by an active phase of collagen suppression during lactation. The third phase of collagen regulation occurred during weaning-induced mammary gland involution, which was characterized by increased collagen deposition. Concomitant changes in collagen protein abundance were confirmed by Masson's trichrome staining, second harmonic generation (SHG) imaging, and mass spectrometry. We observed similar reproductive-state dependent collagen patterns in human breast tissue obtained from premenopausal women. SHG analysis also revealed structural variation in collagen across a reproductive cycle, with higher packing density and more collagen fibers arranged perpendicular to the mammary epithelium in the involuting rat mammary gland compared to nulliparous and lactating glands. Involution was also characterized by high expression of the collagen cross-linking enzyme lysyl oxidase, which was associated with increased levels of cross-linked collagen. Breast cancer relevance is suggested, as we found that breast cancer diagnosed in recently postpartum women displayed gene expression signatures of increased collagen deposition and crosslinking compared to breast cancers diagnosed in age-matched nulliparous women. Using publically available data sets, we found this involution-like, collagen gene signature correlated with poor progression-free survival in breast cancer patients overall and in younger women. In sum, these findings of physiologic collagen regulation in the normal mammary gland may provide insight into normal breast function, the etiology of breast density, and inform breast cancer risk and outcomes.
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33
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Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes. Nat Commun 2021; 12:6341. [PMID: 34732713 PMCID: PMC8566602 DOI: 10.1038/s41467-021-26505-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 10/06/2021] [Indexed: 12/21/2022] Open
Abstract
Young women's breast cancer (YWBC) has poor prognosis and known interactions with parity. Women diagnosed within 5-10 years of childbirth, defined as postpartum breast cancer (PPBC), have poorer prognosis compared to age, stage, and biologic subtype-matched nulliparous patients. Genomic differences that explain this poor prognosis remain unknown. In this study, using RNA expression data from clinically matched estrogen receptor positive (ER+) cases (n = 16), we observe that ER+ YWBC can be differentiated based on a postpartum or nulliparous diagnosis. The gene expression signatures of PPBC are consistent with increased cell cycle, T-cell activation and reduced estrogen receptor and TP53 signaling. When applied to a large YWBC cohort, these signatures for ER+ PPBC associate with significantly reduced 15-year survival rates in high compared to low expressing cases. Cumulatively these results provide evidence that PPBC is a unique entity within YWBC with poor prognostic phenotypes.
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34
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Nwosu IO, Piccolo SR. A systematic review of datasets that can help elucidate relationships among gene expression, race, and immunohistochemistry-defined subtypes in breast cancer. Cancer Biol Ther 2021; 22:417-429. [PMID: 34412551 DOI: 10.1080/15384047.2021.1953902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Scholarly requirements have led to a massive increase of transcriptomic data in the public domain, with millions of samples available for secondary research. We identified gene-expression datasets representing 10,214 breast-cancer patients in public databases. We focused on datasets that included patient metadata on race and/or immunohistochemistry (IHC) profiling of the ER, PR, and HER-2 proteins. This review provides a summary of these datasets and describes findings from 32 research articles associated with the datasets. These studies have helped to elucidate relationships between IHC, race, and/or treatment options, as well as relationships between IHC status and the breast-cancer intrinsic subtypes. We have also identified broad themes across the analysis methodologies used in these studies, including breast cancer subtyping, deriving predictive biomarkers, identifying differentially expressed genes, and optimizing data processing. Finally, we discuss limitations of prior work and recommend future directions for reusing these datasets in secondary analyses.
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Affiliation(s)
| | - Stephen R Piccolo
- Department of Biology, Brigham Young University, Provo, Utah, United States
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35
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Behring M, Ye Y, Elkholy A, Bajpai P, Agarwal S, Kim H, Ojesina AI, Wiener HW, Manne U, Shrestha S, Vazquez AI. Immunophenotype-associated gene signature in ductal breast tumors varies by receptor subtype, but the expression of individual signature genes remains consistent. Cancer Med 2021; 10:5712-5720. [PMID: 34189853 PMCID: PMC8366080 DOI: 10.1002/cam4.4095] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/25/2021] [Accepted: 05/10/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND In silico deconvolution of invasive immune cell infiltration in bulk breast tumors helps characterize immunophenotype, expands treatment options, and influences survival endpoints. In this study, we identify the differential expression (DE) of the LM22 signature to classify immune-rich and -poor breast tumors and evaluate immune infiltration by receptor subtype and lymph node metastasis. METHODS Using publicly available data, we applied the CIBERSORT algorithm to estimate immune cells infiltrating the tumor into immune-rich and immune-poor groups. We then tested the association of receptor subtype and nodal status with immune-rich/poor phenotype. We used DE to test individual signature genes and over-representation analysis for related pathways. RESULTS CCL19 and CXCL9 expression differed between rich/poor signature groups regardless of subtype. Overexpression of CHI3L2 and FES was observed in triple negative breast cancers (TNBCs) relative to other subtypes in immune-rich tumors. Non-signature genes, LYZ, C1QB, CORO1A, EVI2B, GBP1, PSMB9, and CD52 were consistently overexpressed in immune-rich tumors, and SCUBE2 and GRIA2 were associated with immune-poor tumors. Immune-rich tumors had significant upregulation of genes/pathways while none were identified in immune-poor tumors. CONCLUSIONS Overall, the proportion of immune-rich/poor tumors differed by subtype; however, a subset of 10 LM22 genes that marked immune-rich status remained the same across subtype. Non-LM22 genes differentially expressed between the phenotypes suggest that the biologic processes responsible for immune-poor phenotype are not yet well characterized.
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MESH Headings
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/genetics
- Breast Neoplasms/immunology
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/immunology
- Carcinoma, Ductal, Breast/pathology
- Datasets as Topic
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic/immunology
- Humans
- Immunophenotyping
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Up-Regulation/immunology
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Affiliation(s)
- Michael Behring
- Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamALUSA
- Department of Pathology and SurgeryUniversity of Alabama at BirminghamBirminghamALUSA
| | - Yuanfan Ye
- Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamALUSA
| | - Amr Elkholy
- Department of Pathology and SurgeryUniversity of Alabama at BirminghamBirminghamALUSA
| | - Prachi Bajpai
- Department of Pathology and SurgeryUniversity of Alabama at BirminghamBirminghamALUSA
| | - Sumit Agarwal
- Department of Pathology and SurgeryUniversity of Alabama at BirminghamBirminghamALUSA
| | - Hyung‐Gyoon Kim
- Department of Pathology and SurgeryUniversity of Alabama at BirminghamBirminghamALUSA
| | - Akinyemi I. Ojesina
- Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamALUSA
- Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamALUSA
| | - Howard W Wiener
- Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamALUSA
| | - Upender Manne
- Department of Pathology and SurgeryUniversity of Alabama at BirminghamBirminghamALUSA
- Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamALUSA
| | - Sadeep Shrestha
- Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamALUSA
| | - Ana I. Vazquez
- Department of Epidemiology and BiostatisticsMichigan State UniversityEast LansingMIUSA
- Institute for Quantitative Health Science & EngineeringEast LansingMIUSA
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36
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Tsai KW, Chong KH, Li CH, Tu YT, Chen YR, Lee MC, Chan SH, Wang LH, Chang YJ. LOC550643, a Long Non-coding RNA, Acts as Novel Oncogene in Regulating Breast Cancer Growth and Metastasis. Front Cell Dev Biol 2021; 9:695632. [PMID: 34354991 PMCID: PMC8329494 DOI: 10.3389/fcell.2021.695632] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/27/2021] [Indexed: 01/09/2023] Open
Abstract
Metastatic disease is responsible for over 90% of death in patients with breast cancer. Therefore, identifying the molecular mechanisms that regulate metastasis and developing useful therapies are crucial tasks. Long non-coding RNAs (lncRNAs), which are non-coding transcripts with >200 nucleotides, have recently been identified as critical molecules for monitoring cancer progression. This study examined the novel lncRNAs involved in the regulation of tumor progression in breast cancer. This study identified 73 metastasis-related lncRNA candidates from comparison of paired isogenic high and low human metastatic breast cancer cell lines, and their expression levels were verified in clinical tumor samples by using The Cancer Genome Atlas. Among the cell lines, a novel lncRNA, LOC550643, was highly expressed in breast cancer cells. Furthermore, the high expression of LOC550643 was significantly correlated with the poor prognosis of breast cancer patients, especially those with triple-negative breast cancer. Knockdown of LOC550643 inhibited cell proliferation of breast cancer cells by blocking cell cycle progression at S phase. LOC550643 promoted important in vitro metastatic traits such as cell migration and invasion. Furthermore, LOC550643 could inhibit miR-125b-2-3p expression to promote breast cancer cell growth and invasiveness. In addition, by using a xenograft mouse model, we demonstrated that depletion of LOC550643 suppressed the lung metastatic potential of breast cancer cells. Overall, our study shows that LOC550643 plays an important role in breast cancer cell metastasis and growth, and LOC550643 could be a potential diagnosis biomarker and therapeutic target for breast cancer.
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Affiliation(s)
- Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Kian-Hwee Chong
- Division of General Surgery, Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Chao-Hsu Li
- Division of General Surgery, Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ya-Ting Tu
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Yi-Ru Chen
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Ming-Cheng Lee
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Shih-Hsuan Chan
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Lu-Hai Wang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.,Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.,Institute of Molecular Medicine, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Yao-Jen Chang
- Division of General Surgery, Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
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37
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Prognostic value of the 6-gene OncoMasTR test in hormone receptor-positive HER2-negative early-stage breast cancer: Comparative analysis with standard clinicopathological factors. Eur J Cancer 2021; 152:78-89. [PMID: 34090143 DOI: 10.1016/j.ejca.2021.04.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/26/2021] [Accepted: 04/15/2021] [Indexed: 11/20/2022]
Abstract
AIM The aim of the study was to assess the prognostic performance of a 6-gene molecular score (OncoMasTR Molecular Score [OMm]) and a composite risk score (OncoMasTR Risk Score [OM]) and to conduct a within-patient comparison against four routinely used molecular and clinicopathological risk assessment tools: Oncotype DX Recurrence Score, Ki67, Nottingham Prognostic Index and Clinical Risk Category, based on the modified Adjuvant! Online definition and three risk factors: patient age, tumour size and grade. METHODS Biospecimens and clinicopathological information for 404 Irish women also previously enrolled in the Trial Assigning Individualized Options for Treatment [Rx] were provided by 11 participating hospitals, as the primary objective of an independent translational study. Gene expression measured via RT-qPCR was used to calculate OMm and OM. The prognostic value for distant recurrence-free survival (DRFS) and invasive disease-free survival (IDFS) was assessed using Cox proportional hazards models and Kaplan-Meier analysis. All statistical tests were two-sided ones. RESULTS OMm and OM (both with likelihood ratio statistic [LRS] P < 0.001; C indexes = 0.84 and 0.85, respectively) were more prognostic for DRFS and provided significant additional prognostic information to all other assessment tools/factors assessed (all LRS P ≤ 0.002). In addition, the OM correctly classified more patients with distant recurrences (DRs) into the high-risk category than other risk classification tools. Similar results were observed for IDFS. DISCUSSION Both OncoMasTR scores were significantly prognostic for DRFS and IDFS and provided additional prognostic information to the molecular and clinicopathological risk factors/tools assessed. OM was also the most accurate risk classification tool for identifying DR. A concise 6-gene signature with superior risk stratification was shown to increase prognosis reliability, which may help clinicians optimise treatment decisions.
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38
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Li Y, Cook KL, Yu W, Jin L, Bouker KB, Clarke R, Hilakivi-Clarke L. Inhibition of Antiestrogen-Promoted Pro-Survival Autophagy and Tamoxifen Resistance in Breast Cancer through Vitamin D Receptor. Nutrients 2021; 13:nu13051715. [PMID: 34069442 PMCID: PMC8159129 DOI: 10.3390/nu13051715] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 01/07/2023] Open
Abstract
We determined how vitamin D receptor (VDR) is linked to disease outcome in estrogen receptor-positive (ER+) breast cancer patients treated with tamoxifen (TAM). Breast cancer patients (n = 581) in four different datasets were divided into those expressing higher (above median) and lower levels of VDR in pretreatment ER+ tumors. Across all datasets, TAM-treated patients with higher pretreatment tumor VDR expression exhibited significantly longer recurrence-free survival. Ingenuity pathway analysis identified autophagy and unfolded protein response (UPR) as top differentially expressed pathways between high and low VDR-expressing ER+ cancers. Activation of VDR with vitamin D (VitD), either calcitriol or its synthetic analog EB1089, sensitized MCF-7-derived, antiestrogen-resistant LCC9 human breast cancer cells to TAM, and attenuated increased UPR and pro-survival autophagy. Silencing of VDR blocked these effects through the IRE1α-JNK pathway. Further, silencing of VDR impaired sensitivity to TAM in antiestrogen-responsive LCC1 cells, and prevented the effects of calcitriol and EB1089 on UPR and autophagy. In a preclinical mouse model, dietary VitD supplementation induced VDR activation and reduced carcinogen-induced ER+ mammary tumor incidence. In addition, IRE1α-JNK signaling was downregulated and survival autophagy was inhibited in mammary tumors of VitD-supplemented mice. Thus, activation of VDR is predictive of reduced risk of breast cancer recurrence in ER+ patients, possibly by inhibiting antiestrogen-promoted pro-survival autophagy.
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Yin Z, Chen W, Yin J, Sun J, Xie Q, Wu M, Zeng F, Ren H. RIPK1 is a negative mediator in Aquaporin 1-driven triple-negative breast carcinoma progression and metastasis. NPJ Breast Cancer 2021; 7:53. [PMID: 33980862 PMCID: PMC8115349 DOI: 10.1038/s41523-021-00261-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 04/15/2021] [Indexed: 02/05/2023] Open
Abstract
The triple-negative breast carcinoma (TNBC) is the most aggressive subtype of breast cancer. In TNBC, Aquaporin 1 (AQP1), a water-transporting transmembrane protein, is aberrantly enriched in cytoplasm and causes tumor cell death evasion. However, the carcinogenetic bioactivities of cytoplasmic AQP1 cannot be attributed to the canonical "osmotic engine model". In the present study, the receptor-interacting protein kinase 1 (RIPK1), a cell death regulator, was identified to negatively mediate AQP1-driven TNBC progression and metastasis. AQP1 overabundance and RIPK1 depletion occurred in TNBC, which were correlated with aggressive oncological features and poor prognosis. AQP1 bound with RIPK1, resulting in the inhibition of RIPK1/RIPK3/MLKL-mediated necroptosis and RIPK1/caspase-8/caspase-3-mediated apoptosis. Genetic inhibition of RIPK1 significantly exacerbated the pro-tumor effect of AQP1, while ectopic expression of RIPK1 notably blunted AQP1 signaling. Mechanistically, AQP1 binds to the D324 site of RIPK1, and facilitates RIPK1 cleavage and inactivation by excessively activating the caspase-8/RIPK1 negative feedback loop. RIPK1D324K overexpression significantly prevented RIPK1 cleavage and weakened the aggressiveness of AQP1-enriched TNBC cells. Overall, our findings clarify the underlying mechanism of cytoplasmic AQP1-driven TNBC progression and metastasis, in which RIPK1 exerts an essential role as a negative mediator and exhibits the potential as a therapeutic target for TNBC.
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Affiliation(s)
- Zhuming Yin
- Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer; Sino-Russian Joint Research Center for Oncoplastic Breast Surgery, Tianjin, China
| | - Wenlin Chen
- Department of Breast Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jian Yin
- Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer; Sino-Russian Joint Research Center for Oncoplastic Breast Surgery, Tianjin, China
| | - Jingyan Sun
- Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer; Sino-Russian Joint Research Center for Oncoplastic Breast Surgery, Tianjin, China
| | - Qianrong Xie
- Department of Clinical Research Center, Dazhou Central Hospital, Dazhou, China
| | - Min Wu
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, China
| | - Fanxin Zeng
- Department of Clinical Research Center, Dazhou Central Hospital, Dazhou, China.
| | - Huiwen Ren
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
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40
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Elevated long noncoding RNA MALAT-1 expression is predictive of poor prognosis in patients with breast cancer: a meta-analysis. Biosci Rep 2021; 40:225866. [PMID: 32700729 PMCID: PMC7419804 DOI: 10.1042/bsr20200215] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 07/08/2020] [Accepted: 07/21/2020] [Indexed: 12/29/2022] Open
Abstract
Accumulating evidence indicates that aberrant regulation of metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), a long noncoding RNA (lncRNA), plays a vital role in tumorigenesis. However, its association with breast cancer has not been systematically evaluated. In the current study, a meta-analysis was conducted to clarify the association between MALAT-1 and the prognosis and clinicopathological features of breast cancer. Relevant literature published in several databases was searched. Hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were calculated to evaluate the effect of MALAT-1 expression on the survival outcomes and clinicopathological features of breast cancer. A total of 12 studies involving 4106 patients were identified. Pooled HR demonstrated that elevated MALAT-1 expression significantly predicted unfavorable overall survival (HR = 2.06, 95% CI: 1.66–2.56, P<0.0001) in patients with breast cancer. Subgroup analysis stratified by cancer type, sample size, and method of variance analysis also showed statistically significant associations. Additionally, the HR of patients with up-regulated MALAT-1 expression concerning disease-free survival (DFS), recurrence-free survival (RFS), and disease-specific survival (DSS) was 1.91 (95% CI: 1.53–2.39, P<0.0001). Further, elevated MALAT-1 expression was positively correlated with the progesterone receptor (PR) status (OR = 1.47, 95% CI: 1.18–1.82). Thus, MALAT-1 is a promising biomarker for predicting survival outcomes in patients with breast cancer.
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Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer. Cancers (Basel) 2021; 13:cancers13051132. [PMID: 33800852 PMCID: PMC7961649 DOI: 10.3390/cancers13051132] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 01/16/2023] Open
Abstract
Simple Summary Overactivation of the human epidermal growth factor receptor 2 (HER2) is one of the main drivers of tamoxifen resistance in estrogen receptor (ER)-positive breast cancer patients. Combined targeting of HER2 and ER, however, has yielded disappointing results in the clinical setting. Therefore, other potential mechanisms for tamoxifen resistance would not be overcome by solely blocking the cross-talk between ER and HER2 at the receptor(s) level. Using cell lines, animal models, and clinical data, we provide evidence to support a critical role of fatty acid synthase (FASN)—the major site for endogenous fat synthesis—in HER2-driven tamoxifen resistance. Importantly, treatment with a FASN inhibitor impeded the estrogen-like tumor-promoting effects of tamoxifen and fully restored the anti-estrogenic activity of tamoxifen in ER+/HER2-overexpressing breast cancer xenografts. We postulate FASN as a biological determinant of HER2-driven tamoxifen resistance and FASN inhibition as a novel therapeutic approach to restore tamoxifen sensitivity in endocrine-resistant breast cancer. Abstract The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity—an in vitro metric of tumorigenicity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.
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Mass-spectrometry-based proteomic correlates of grade and stage reveal pathways and kinases associated with aggressive human cancers. Oncogene 2021; 40:2081-2095. [PMID: 33627787 PMCID: PMC7981264 DOI: 10.1038/s41388-021-01681-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/11/2021] [Accepted: 01/25/2021] [Indexed: 01/30/2023]
Abstract
Proteomic signatures associated with clinical measures of more aggressive cancers could yield molecular clues as to disease drivers. Here, utilizing the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets, we defined differentially expressed proteins and mRNAs associated with higher grade or higher stage, for each of seven cancer types (breast, colon, lung adenocarcinoma, clear cell renal, ovarian, uterine, and pediatric glioma), representing 794 patients. Widespread differential patterns of total proteins and phosphoproteins involved some common patterns shared between different cancer types. More proteins were associated with higher grade than higher stage. Most proteomic signatures predicted patient survival in independent transcriptomic datasets. The proteomic grade signatures, in particular, involved DNA copy number alterations. Pathways of interest were enriched within the grade-associated proteins across multiple cancer types, including pathways of altered metabolism, Warburg-like effects, and translation factors. Proteomic grade correlations identified protein kinases having functional impact in vitro in uterine endometrial cancer cells, including MAP3K2, MASTL, and TTK. The protein-level grade and stage associations for all proteins profiled-along with corresponding information on phosphorylation, pathways, mRNA expression, and copy alterations-represent a resource for identifying new potential targets. Proteomic analyses are often concordant with corresponding transcriptomic analyses, but with notable exceptions.
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Dong M, Xu T, Cui X, Li H, Li X, Xia W. NCAPG upregulation mediated by four microRNAs combined with activation of the p53 signaling pathway is a predictor of poor prognosis in patients with breast cancer. Oncol Lett 2021; 21:323. [PMID: 33692855 PMCID: PMC7933778 DOI: 10.3892/ol.2021.12585] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023] Open
Abstract
The role of non-SMC condensin I complex subunit G (NCAPG) in breast cancer remains unclear. The present study used online databases, reverse transcription-quantitative PCR, flow cytometry and western blotting to determine the expression levels, prognosis and potential molecular mechanisms underlying the role of NCAPG in breast cancer. The association between NCAPG expression and several different clinicopathological parameters in patients with breast cancer was determined, and the results revealed that NCAPG expression was negatively associated with estrogen receptor and progesterone receptor positive status, but was positively associated with HER2 positive status, Nottingham Prognostic Index score and Scarff-Bloom-Richardson grade status. Furthermore, upregulated expression levels of NCAPG resulted in a poor prognosis in patients with breast cancer. A total of 27 microRNAs (miRNAs/miRs) were predicted to target NCAPG, among which four miRNAs (miR-101-3p, miR-195-5p, miR-214-3p and miR-944) were predicted to most likely regulate NCAPG expression in breast cancer. A total of 261 co-expressed genes of NCAPG were identified, including cell division cyclin 25 homolog C (CDC25C), and pathway enrichment analysis indicated that these co-expressed genes were significantly enriched in the p53 signaling pathway. CDC25C expression was downregulated in breast cancer and was associated with a poor prognosis. These findings suggested that upregulated NCAPG expression may be a prognostic biomarker of breast cancer.
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Affiliation(s)
- Menglu Dong
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Tao Xu
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Xiaoqing Cui
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Hanning Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Xingrui Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Wenfei Xia
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Bou Zerdan M, Ibrahim M, El Nakib C, Hajjar R, Assi HI. Genomic Assays in Node Positive Breast Cancer Patients: A Review. Front Oncol 2021; 10:609100. [PMID: 33665165 PMCID: PMC7921691 DOI: 10.3389/fonc.2020.609100] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/30/2020] [Indexed: 01/16/2023] Open
Abstract
In recent years, developments in breast cancer have allowed yet another realization of individualized medicine in the field of oncology. One of these advances is genomic assays, which are considered elements of standard clinical practice in the management of breast cancer. These assays are widely used today not only to measure recurrence risk in breast cancer patients at an early stage but also to tailor treatment as well and minimize avoidable treatment side effects. At present, genomic tests are applied extensively in node negative disease. In this article, we review the use of these tests in node positive disease, explore their ramifications on neoadjuvant chemotherapy decisions, highlight sufficiently powered recent studies emphasizing their use and review the most recent guidelines.
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Affiliation(s)
- Maroun Bou Zerdan
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon
| | - Maryam Ibrahim
- Division of Internal Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Clara El Nakib
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rayan Hajjar
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon
| | - Hazem I. Assi
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon
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45
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Wang X, Veeraraghavan J, Liu CC, Cao X, Qin L, Kim JA, Tan Y, Loo SK, Hu Y, Lin L, Lee S, Shea MJ, Mitchell T, Li S, Ellis MJ, Hilsenbeck SG, Schiff R, Wang XS. Therapeutic Targeting of Nemo-like Kinase in Primary and Acquired Endocrine-resistant Breast Cancer. Clin Cancer Res 2021; 27:2648-2662. [PMID: 33542078 DOI: 10.1158/1078-0432.ccr-20-2961] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 11/29/2020] [Accepted: 02/01/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Endocrine resistance remains a major clinical challenge in estrogen receptor (ER)-positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here, we report Nemo-like kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine-resistant breast cancer. EXPERIMENTAL DESIGN The effects of NLK inhibition on the viability of endocrine-resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator, SRC-3, by NLK was examined by immunoprecipitation, kinase assay, luciferase assay, and RNA sequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patient-derived xenograft (PDX) tumor models. RESULTS NLK overexpression endows reduced endocrine responsiveness and is associated with worse outcome of patients treated with tamoxifen. Mechanistically, NLK may function, at least in part, via enhancing the phosphorylation of ERα and its key coactivator, SRC-3, to modulate ERα transcriptional activity. Through interrogation of a kinase profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Coadministration of VX-702 with the mTOR inhibitor, everolimus, demonstrated a significant therapeutic effect in cell line-derived xenograft and PDX tumor models of acquired or de novo endocrine resistance. CONCLUSIONS Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling.
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Affiliation(s)
- Xian Wang
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Women's Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania.,Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Jamunarani Veeraraghavan
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Chia-Chia Liu
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Women's Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania
| | - Xixi Cao
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Lanfang Qin
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Jin-Ah Kim
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Ying Tan
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Suet Kee Loo
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Women's Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania
| | - Yiheng Hu
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Women's Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania.,Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Ling Lin
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Women's Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania
| | - Sanghoon Lee
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Martin J Shea
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Tamika Mitchell
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Shunqiang Li
- Department of Medicine, Washington University School of Medicine at St Louis, St. Louis, Missouri
| | - Matthew J Ellis
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Susan G Hilsenbeck
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Rachel Schiff
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Xiao-Song Wang
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania. .,Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Women's Cancer Research Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania.,Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas.,Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
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Hickey TE, Selth LA, Chia KM, Laven-Law G, Milioli HH, Roden D, Jindal S, Hui M, Finlay-Schultz J, Ebrahimie E, Birrell SN, Stelloo S, Iggo R, Alexandrou S, Caldon CE, Abdel-Fatah TM, Ellis IO, Zwart W, Palmieri C, Sartorius CA, Swarbrick A, Lim E, Carroll JS, Tilley WD. The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer. Nat Med 2021; 27:310-320. [PMID: 33462444 DOI: 10.1038/s41591-020-01168-7] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/03/2020] [Indexed: 01/28/2023]
Abstract
The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.
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Affiliation(s)
- Theresa E Hickey
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Luke A Selth
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia
- Freemason's Foundation Centre for Men's Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Kee Ming Chia
- Garvan Institute of Medical Research & St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Geraldine Laven-Law
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Heloisa H Milioli
- Garvan Institute of Medical Research & St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Daniel Roden
- Garvan Institute of Medical Research & St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Shalini Jindal
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Mun Hui
- Garvan Institute of Medical Research & St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | | | - Esmaeil Ebrahimie
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Stephen N Birrell
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Suzan Stelloo
- Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
- Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands
| | - Richard Iggo
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Institut Bergonié, University of Bordeaux, Bordeaux, France
| | - Sarah Alexandrou
- Garvan Institute of Medical Research & St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - C Elizabeth Caldon
- Garvan Institute of Medical Research & St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | | | | | - Wilbert Zwart
- Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Carlo Palmieri
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool & Clatterbridge Centre NHS Foundation Trust, Liverpool, UK
| | | | - Alex Swarbrick
- Garvan Institute of Medical Research & St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Elgene Lim
- Garvan Institute of Medical Research & St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Jason S Carroll
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Wayne D Tilley
- Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
- Freemason's Foundation Centre for Men's Health, University of Adelaide, Adelaide, South Australia, Australia.
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Johansson ALV, Trewin CB, Fredriksson I, Reinertsen KV, Russnes H, Ursin G. In modern times, how important are breast cancer stage, grade and receptor subtype for survival: a population-based cohort study. Breast Cancer Res 2021; 23:17. [PMID: 33526044 PMCID: PMC7852363 DOI: 10.1186/s13058-021-01393-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 01/14/2021] [Indexed: 12/20/2022] Open
Abstract
Background In breast cancer, immunohistochemistry (IHC) subtypes, together with grade and stage, are well-known independent predictors of breast cancer death. Given the immense changes in breast cancer treatment and survival over time, we used recent population-based data to test the combined influence of IHC subtypes, grade and stage on breast cancer death. Methods We identified 24,137 women with invasive breast cancer aged 20 to 74 between 2005 and 2015 in the database of the Cancer Registry of Norway. Kaplan-Meier curves, mortality rates and adjusted hazard ratios for breast cancer death were estimated by IHC subtypes, grade, tumour size and nodal status during 13 years of follow-up. Results Within all IHC subtypes, grade, tumour size and nodal status were independent predictors of breast cancer death. When combining all prognostic factors, the risk of death was 20- to 40-fold higher in the worst groups compared to the group with the smallest size, low grade and ER+PR+HER2− status. Among node-negative ER+HER2− tumours, larger size conferred a significantly increased breast cancer mortality. ER+PR−HER2− tumours of high grade and advanced stage showed particularly high breast cancer mortality similar to TNBC. When examining early versus late mortality, grade, size and nodal status explained most of the late (> 5 years) mortality among ER+ subtypes. Conclusions There is a wide range of risks of dying from breast cancer, also across small breast tumours of low/intermediate grade, and among node-negative tumours. Thus, even with modern breast cancer treatment, stage, grade and molecular subtype (reflected by IHC subtypes) matter for prognosis. Supplementary Information The online version contains supplementary material available at 10.1186/s13058-021-01393-z.
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Affiliation(s)
- Anna L V Johansson
- Cancer Registry of Norway, Oslo, Norway. .,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, P.O.Box 281, SE-17177, Stockholm, Sweden.
| | - Cassia B Trewin
- Department of Registration, Cancer Registry of Norway, Oslo, Norway
| | - Irma Fredriksson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Breast and Endocrine Surgery, Karolinska University Hospital Solna, Stockholm, Sweden
| | | | - Hege Russnes
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Giske Ursin
- Cancer Registry of Norway, Oslo, Norway.,Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.,Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
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48
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Supplitt S, Karpinski P, Sasiadek M, Laczmanska I. Current Achievements and Applications of Transcriptomics in Personalized Cancer Medicine. Int J Mol Sci 2021; 22:1422. [PMID: 33572595 PMCID: PMC7866970 DOI: 10.3390/ijms22031422] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/12/2022] Open
Abstract
Over the last decades, transcriptome profiling emerged as one of the most powerful approaches in oncology, providing prognostic and predictive utility for cancer management. The development of novel technologies, such as revolutionary next-generation sequencing, enables the identification of cancer biomarkers, gene signatures, and their aberrant expression affecting oncogenesis, as well as the discovery of molecular targets for anticancer therapies. Transcriptomics contribute to a change in the holistic understanding of cancer, from histopathological and organic to molecular classifications, opening a more personalized perspective for tumor diagnostics and therapy. The further advancement on transcriptome profiling may allow standardization and cost reduction of its analysis, which will be the next step for transcriptomics to become a canon of contemporary cancer medicine.
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Affiliation(s)
- Stanislaw Supplitt
- Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland; (P.K.); (M.S.); (I.L.)
| | - Pawel Karpinski
- Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland; (P.K.); (M.S.); (I.L.)
- Laboratory of Genomics and Bioinformatics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wroclaw, Poland
| | - Maria Sasiadek
- Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland; (P.K.); (M.S.); (I.L.)
| | - Izabela Laczmanska
- Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland; (P.K.); (M.S.); (I.L.)
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49
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Polytarchou C, Hatziapostolou M, Yau TO, Christodoulou N, Hinds PW, Kottakis F, Sanidas I, Tsichlis PN. Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47 phox. Proc Natl Acad Sci U S A 2020; 117:28806-28815. [PMID: 33139577 PMCID: PMC7682348 DOI: 10.1073/pnas.2017830117] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Akt activation up-regulates the intracellular levels of reactive oxygen species (ROS) by inhibiting ROS scavenging. Of the Akt isoforms, Akt3 has also been shown to up-regulate ROS by promoting mitochondrial biogenesis. Here, we employ a set of isogenic cell lines that express different Akt isoforms, to show that the most robust inducer of ROS is Akt3. As a result, Akt3-expressing cells activate the DNA damage response pathway, express high levels of p53 and its direct transcriptional target miR-34, and exhibit a proliferation defect, which is rescued by the antioxidant N-acetylcysteine. The importance of the DNA damage response in the inhibition of cell proliferation by Akt3 was confirmed by Akt3 overexpression in p53-/- and INK4a-/-/Arf-/- mouse embryonic fibroblasts (MEFs), which failed to inhibit cell proliferation, despite the induction of high levels of ROS. The induction of ROS by Akt3 is due to the phosphorylation of the NADPH oxidase subunit p47phox, which results in NADPH oxidase activation. Expression of Akt3 in p47phox-/- MEFs failed to induce ROS and to inhibit cell proliferation. Notably, the proliferation defect was rescued by wild-type p47phox, but not by the phosphorylation site mutant of p47phox In agreement with these observations, Akt3 up-regulates p53 in human cancer cell lines, and the expression of Akt3 positively correlates with the levels of p53 in a variety of human tumors. More important, Akt3 alterations correlate with a higher frequency of mutation of p53, suggesting that tumor cells may adapt to high levels of Akt3, by inactivating the DNA damage response.
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Affiliation(s)
- Christos Polytarchou
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
- Department of Biosciences, John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, NG11 8NS Nottingham, United Kingdom
- Centre for Health, Aging and Understanding Disease, Nottingham Trent University, NG11 8NS Nottingham, United Kingdom
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111
| | - Maria Hatziapostolou
- Department of Biosciences, John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, NG11 8NS Nottingham, United Kingdom
- Centre for Health, Aging and Understanding Disease, Nottingham Trent University, NG11 8NS Nottingham, United Kingdom
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111
| | - Tung On Yau
- Department of Biosciences, John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, NG11 8NS Nottingham, United Kingdom
- Centre for Health, Aging and Understanding Disease, Nottingham Trent University, NG11 8NS Nottingham, United Kingdom
| | - Niki Christodoulou
- Department of Biosciences, John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, NG11 8NS Nottingham, United Kingdom
- Centre for Health, Aging and Understanding Disease, Nottingham Trent University, NG11 8NS Nottingham, United Kingdom
| | - Philip W Hinds
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111
- Department of Developmental, Molecular and Chemical Biology, Tufts Cancer Center, Tufts University School of Medicine, Boston, MA 02111
| | - Filippos Kottakis
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111
| | - Ioannis Sanidas
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111
- Department of Medicine, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129
| | - Philip N Tsichlis
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111
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Rahem SM, Epsi NJ, Coffman FD, Mitrofanova A. Genome-wide analysis of therapeutic response uncovers molecular pathways governing tamoxifen resistance in ER+ breast cancer. EBioMedicine 2020; 61:103047. [PMID: 33099086 PMCID: PMC7585053 DOI: 10.1016/j.ebiom.2020.103047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 09/02/2020] [Accepted: 09/18/2020] [Indexed: 01/10/2023] Open
Abstract
Background Prioritization of breast cancer patients based on the risk of resistance to tamoxifen plays a significant role in personalized therapeutic planning and improving disease course and outcomes. Methods In this work, we demonstrate that a genome-wide pathway-centric computational framework elucidates molecular pathways as markers of tamoxifen resistance in ER+ breast cancer patients. In particular, we associated activity levels of molecular pathways with a wide spectrum of response to tamoxifen, which defined markers of tamoxifen resistance in patients with ER+ breast cancer. Findings We identified five biological pathways as markers of tamoxifen failure and demonstrated their ability to predict the risk of tamoxifen resistance in two independent patient cohorts (Test cohort1: log-rank p-value = 0.02, adjusted HR = 3.11; Test cohort2: log-rank p-value = 0.01, adjusted HR = 4.24). We have shown that these pathways are not markers of aggressiveness and outperform known markers of tamoxifen response. Furthermore, for adoption into clinic, we derived a list of pathway read-out genes and their associated scoring system, which assigns a risk of tamoxifen resistance for new incoming patients. Interpretation We propose that the identified pathways and their read-out genes can be utilized to prioritize patients who would benefit from tamoxifen treatment and patients at risk of tamoxifen resistance that should be offered alternative regimens. Funding This work was supported by the Rutgers SHP Dean's research grant, Rutgers start-up funds, Libyan Ministry of Higher Education and Scientific Research, and Katrina Kehlet Graduate Award from The NJ Chapter of the Healthcare Information Management Systems Society.
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Affiliation(s)
- Sarra M Rahem
- Department of Biomedical and Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, USA
| | - Nusrat J Epsi
- Department of Biomedical and Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, USA
| | - Frederick D Coffman
- Department of Biomedical and Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, USA; Department of Physician Assistant Studies and Practice, USA; Department of Pathology & Laboratory Medicine, New Jersey Medical School, Newark, New Jersey 07107, USA
| | - Antonina Mitrofanova
- Department of Biomedical and Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, USA; Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901, USA.
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