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1
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Liu Y, Zou Y, Ye Y, Chen Y. Advances in the Understanding of the Pathogenesis of Triple-Negative Breast Cancer. Cancer Med 2024; 13:e70410. [PMID: 39558881 PMCID: PMC11574469 DOI: 10.1002/cam4.70410] [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: 09/02/2024] [Revised: 10/24/2024] [Accepted: 10/30/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by high aggressiveness, high malignancy, and poor prognosis compared to other breast cancer subtypes. OBJECTIVE This review aims to explore recent advances in understanding TNBC and to provide new insights and potential references for clinical treatment. METHODS We examined current literature on TNBC to analyze molecular subtypes, genetic mutations, signaling pathways, mechanisms of drug resistance, and emerging therapies. RESULTS Findings highlight key aspects of TNBC's molecular subtypes, relevant mutations, and pathways, alongside emerging treatments that target drug resistance mechanisms. CONCLUSION These insights into TNBC pathogenesis may help guide future therapeutic strategies and improve clinical outcomes for patients with TNBC.
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Affiliation(s)
- Yuhan Liu
- School of Clinical MedicineShandong Second Medical UniversityWeifangChina
| | - Yuhan Zou
- School of Clinical MedicineShandong Second Medical UniversityWeifangChina
| | - Yangli Ye
- College of Life Sciences and TechnologyShandong Second Medical UniversityWeifangChina
| | - Yong Chen
- Key Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, School of Basic Medical SciencesShandong Second Medical UniversityWeifangChina
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2
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Pan C, Dai J, Wei Y, Yang L, Ding Z, Wang X, He J. Matrix Metalloproteinase 11 Promotes Migration and Invasion of Colorectal Cancer by Elevating Slug Protein. Int J Med Sci 2024; 21:2170-2188. [PMID: 39239548 PMCID: PMC11373555 DOI: 10.7150/ijms.98007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 08/03/2024] [Indexed: 09/07/2024] Open
Abstract
Purpose: Matrix metalloproteinase-11 (MMP11), which belongs to the stromelysin subgroup, has been reported to play a role in the progression of colorectal cancer (CRC). However, the significance of MMP11 in the tumor microenvironment, immune/stromal cells, and its mechanism in CRC remain unclear. Methods: The impact of MMP11 knockdown using specific short hairpin RNAs (shRNAs) on the metastasis and invasion of colorectal cancer RKO and SW480 cells was investigated using western blot, quantitative real-time polymerase chain reaction (qRT-PCR), transwell assays, and immunohistochemistry. Results: MMP11 mRNA expression was significantly higher in CRC cells than in normal cells, and its expression was stimulated in CCD-18Co fibroblasts. Additionally, MMP11 expression was found to be higher in individuals aged ≤ 65 years, the T4/T3 group, and Stage III/IV patients. Overall survival (OS) and disease-free survival rates were significantly different between the high and low MMP11 groups. Furthermore, the receiver operating characteristic (ROC) curves for MMP11 at 1-, 3-, and 5-years were 0.450, 0.552, and 0.560, respectively. Moreover, MMP11 promoted the migration and invasion of CRC cells by elevating the expression of Slug protein. Most importantly, MMP11 was positively associated with M0-macrophages and negatively associated with M1-macrophages, NK cells activated, NK cells resting, T cells CD4 memory activated, and T cells follicular helper, indicating the remarkable interactions of MMP11 with tumor immunology. Conclusions: MMP11 plays an important role in colorectal cancer development, and its mechanism in CRC needs to be further explored in the future.
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Affiliation(s)
- Chaomin Pan
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingping Dai
- Department of Gastroenterology, Longgang Central Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - Yiyi Wei
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Li Yang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhuoyu Ding
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinke Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Juan He
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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3
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Jan N, Sofi S, Qayoom H, Haq BU, Shabir A, Mir MA. Targeting breast cancer stem cells through retinoids: A new hope for treatment. Crit Rev Oncol Hematol 2023; 192:104156. [PMID: 37827439 DOI: 10.1016/j.critrevonc.2023.104156] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 09/09/2023] [Accepted: 10/06/2023] [Indexed: 10/14/2023] Open
Abstract
Breast cancer is a complex and diverse disease accounting for nearly 30% of all cancers diagnosed in females. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. With over half a million deaths annually, it is imperative to explore new therapeutic approaches to combat the disease. Within a breast tumor, a small sub-population of heterogeneous cells, with a unique ability of self-renew and differentiation and responsible for tumor formation, initiation, and recurrence are referred to as breast cancer stem cells (BCSCs). These BCSCs have been identified as one of the main contributors to chemoresistance in breast cancer, making them an attractive target for developing novel therapeutic strategies. These cells exhibit surface biomarkers such as CD44+, CD24-/LOW, ALDH, CD133, and CD49f phenotypes. Higher expression of CD44+ and ALDH activity has been associated with the formation of tumors in various cancers. Moreover, the abnormal regulation of signaling pathways, including Hedgehog, Notch, β-catenin, JAK/STAT, and P13K/AKT/mTOR, leads to the formation of cancer stem cells, resulting in the development of tumors. The growing drug resistance in BC is a significant challenge, highlighting the need for new therapeutic strategies to combat this dreadful disease. Retinoids, a large group of synthetic derivatives of vitamin A, have been studied as chemopreventive agents in clinical trials and have been shown to regulate various crucial biological functions including vision, development, inflammation, and metabolism. On a cellular level, the retinoid activity has been well characterized and translated and is known to induce differentiation and apoptosis, which play important roles in the outcome of the transformation of tissues into malignant. Retinoids have been investigated extensively for their use in the treatment and prevention of cancer due to their high receptor-binding affinity to directly modulate gene expression programs. Therefore, in this study, we aim to summarize the current understanding of BCSCs, their biomarkers, and the associated signaling pathways. Retinoids, such as Adapalene, a third-generation retinoid, have shown promising anti-cancer potential and may serve as therapeutic agents to target BCSCs.
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Affiliation(s)
- Nusrat Jan
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Shazia Sofi
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Hina Qayoom
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Burhan Ul Haq
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Aisha Shabir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Manzoor Ahmad Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India.
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4
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Githaka JM, Pirayeshfard L, Goping IS. Cancer invasion and metastasis: Insights from murine pubertal mammary gland morphogenesis. Biochim Biophys Acta Gen Subj 2023; 1867:130375. [PMID: 37150225 DOI: 10.1016/j.bbagen.2023.130375] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 04/20/2023] [Accepted: 05/02/2023] [Indexed: 05/09/2023]
Abstract
Cancer invasion and metastasis accounts for the majority of cancer related mortality. A better understanding of the players that drive the aberrant invasion and migration of tumors cells will provide critical targets to inhibit metastasis. Postnatal pubertal mammary gland morphogenesis is characterized by highly proliferative, invasive, and migratory normal epithelial cells. Identifying the molecular regulators of pubertal gland development is a promising strategy since tumorigenesis and metastasis is postulated to be a consequence of aberrant reactivation of developmental stages. In this review, we summarize the pubertal morphogenesis regulators that are involved in cancer metastasis and revisit pubertal mammary gland transcriptome profiling to uncover both known and unknown metastasis genes. Our updated list of pubertal morphogenesis regulators shows that most are implicated in invasion and metastasis. This review highlights molecular linkages between development and metastasis and provides a guide for exploring novel metastatic drivers.
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Affiliation(s)
- John Maringa Githaka
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
| | - Leila Pirayeshfard
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Ing Swie Goping
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; Department of Oncology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
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GLI1 interaction with p300 modulates SDF1 expression in cancer-associated fibroblasts to promote pancreatic cancer cells migration. Biochem J 2023; 480:225-241. [PMID: 36734208 DOI: 10.1042/bcj20220521] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 02/02/2023] [Accepted: 02/02/2023] [Indexed: 02/04/2023]
Abstract
Carcinoma-associated fibroblasts (CAFs) play an important role in the progression of multiple malignancies. Secretion of cytokines and growth factors underlies the pro-tumoral effect of CAFs. Although this paracrine function has been extensively documented, the molecular mechanisms controlling the expression of these factors remain elusive. In this study, we provide evidence of a novel CAF transcriptional axis regulating the expression of SDF1, a major driver of cancer cell migration, involving the transcription factor GLI1 and histone acetyltransferase p300. We demonstrate that conditioned media from CAFs overexpressing GLI1 induce the migration of pancreatic cancer cells, and this effect is impaired by an SDF1-neutralizing antibody. Using a combination of co-immunoprecipitation, proximity ligation assay and chromatin immunoprecipitation assay, we further demonstrate that GLI1 and p300 physically interact in CAFs to co-occupy and drive SDF1 promoter activity. Mapping experiments highlight the requirement of GLI1 N-terminal for the interaction with p300. Importantly, knockdowns of both GLI1 and p300 reduce SDF1 expression. Further analysis shows that knockdown of GLI1 decreases SDF1 promoter activity, p300 recruitment, and levels of its associated histone marks (H4ac, H3K27ac, and H3K14ac). Finally, we show that the integrity of two GLI binding sites in the SDF1 promoter is required for p300 recruitment. Our findings define a new role for the p300-GLI1 complex in the regulation of SDF1, providing new mechanistic insight into the molecular events controlling pancreatic cancer cells migration.
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Subhan MA. Advances with metal oxide-based nanoparticles as MDR metastatic breast cancer therapeutics and diagnostics. RSC Adv 2022; 12:32956-32978. [PMID: 36425155 PMCID: PMC9670683 DOI: 10.1039/d2ra02005j] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 11/08/2022] [Indexed: 11/18/2022] Open
Abstract
Metal oxide nanoparticles have attracted increased attention due to their emerging applications in cancer detection and therapy. This study envisioned to highlight the great potential of metal oxide NPs due to their interesting properties including high payload, response to magnetic field, affluence of surface modification to overcome biological barriers, and biocompatibility. Mammogram, ultrasound, X-ray computed tomography (CT), MRI, positron emission tomography (PET), optical or fluorescence imaging are used for breast imaging. Drug-loaded metal oxide nanoparticle delivered to the breast cancer cells leads to higher drug uptake. Thus, enhanced the cytotoxicity to target cells compared to free drug. The drug loaded metal oxide nanoparticle formulations hold great promise to enhance efficacy of breast cancer therapy including multidrug resistant (MDR) and metastatic breast cancers. Various metal oxides including magnetic metal oxides and magnetosomes are of current interests to explore cancer drug delivery and diagnostic efficacy especially for metastatic breast cancer. Metal oxide-based nanocarrier formulations are promising for their usage in drug delivery and release to breast cancer cells, cancer diagnosis and their clinical translations. Biomarker targeted therapy approaches for TNBC using metal oxide-based NPs are highly effective and promising.![]()
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Affiliation(s)
- Md Abdus Subhan
- Department of Chemistry, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
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7
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The tamoxifen-regulated, long non-coding RNA LINC00992 affects proliferation, migration, and expression of tamoxifen resistance-associated genes in MCF-7 breast cancer cells. Contemp Oncol (Pozn) 2022; 26:294-305. [PMID: 36816389 PMCID: PMC9933353 DOI: 10.5114/wo.2023.125000] [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: 01/26/2023] [Accepted: 01/29/2023] [Indexed: 02/12/2023] Open
Abstract
Introduction Tamoxifen-adapted MCF-7 breast cancer cells (MCF-7-TAM-R) are a model for acquired tamoxifen resistance in oestrogen receptor-positive breast cancer. In this system, the expression of long-non-coding RNA LINC00992 is decreased. LINC00992 might therefore contribute to tamoxifen adaption and associated gene expres-sion changes. Here, we investigated whether a modulation of LINC00992 modifies gene expression, proliferation, and migration. Material and methods Up- and down-- regulation of LINC00992 was performed using plasmid vectors and siRNA. Gene expression was measured via nCounter® and quantitative real-time polymerase chain reaction. Database analysis was performed using GEPIA2 and cBioportal. Furthermore, we performed scratch assays, colony-forming assays, and proliferation assays with MCF-7 and MCF-7-TAM-R after up-regulation of LINC00992. Results Up- and down-regulation of LINC00992 caused gene expression changes in 4 of the 42 tamoxifen-regulated genes tested. Especially ubiquitin D, single-minded homologue 1 (SIM1) carcinoembryonic antigen-related cell adhesion molecule 5 and the G-protein coupled oestrogen receptor 1 were affected. In tamoxifen-adapted MCF-7-TAM-R cells, LINC00992 overexpression resulted in augmented viability and proliferation and enhanced migration. Database analyses revealed that luminal breast cancers have increased expression of LINC00992 compared to Her2-type/neu- or basal type. Furthermore, higher expression of LINC00992 was associated with poor prognosis in luminal-A carcinomas. Conclusions Changes in the expression of tamoxifen-regulated genes could be induced by manipulating LINC00992's abundance, suggesting that it is at least partially involved in the establishment of the tamoxifen-induced gene expression pattern. LINC00992 may also serve as a prognostic biomarker and may indicate the development of tamoxifen resistance.
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Molecular targets and therapeutics in chemoresistance of triple-negative breast cancer. Med Oncol 2021; 39:14. [PMID: 34812991 DOI: 10.1007/s12032-021-01610-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023]
Abstract
Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer (BC), which shows immunohistochemically negative expression of hormone receptor i.e., Estrogen receptor and Progesterone receptor along with the absence of Human Epidermal Growth Factor Receptor-2 (HER2/neu). In Indian scenario the prevalence of BC is 26.3%, whereas, in West Bengal the cases are of 18.4%. But the rate of TNBC has increased up to 31% and shows 27% of total BC. Conventional chemotherapy is effective only in the initial stages but with progression of the disease the effectivity gets reduced and shown almost no effect in later or advanced stages of TNBC. Thus, TNBC patients frequently develop resistance and metastasis, due to its peculiar triple-negative nature most of the hormonal therapies also fails. Development of chemoresistance may involve various factors, such as, TNBC heterogeneity, cancer stem cells (CSCs), signaling pathway deregulation, DNA repair mechanism, hypoxia, and other molecular factors. To overcome the challenges to treat TNBC various targets and molecules have been exploited including CSCs modulator, drug efflux transporters, hypoxic factors, apoptotic proteins, and regulatory signaling pathways. Moreover, to improve the targets and efficacy of treatments researchers are emphasizing on targeted therapy for TNBC. In this review, an effort has been made to focus on phenotypic and molecular variations in TNBC along with the role of conventional as well as newly identified pathways and strategies to overcome challenge of chemoresistance.
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9
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Mani C, Tripathi K, Omy TR, Reedy M, Manne U, Palle K. GLI1-targeting drugs induce replication stress and homologous recombination deficiency and synergize with PARP-targeted therapies in triple negative breast cancer cells. Biochim Biophys Acta Mol Basis Dis 2021; 1868:166300. [PMID: 34748904 DOI: 10.1016/j.bbadis.2021.166300] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/20/2021] [Accepted: 11/03/2021] [Indexed: 01/20/2023]
Abstract
Triple negative breast cancer (TNBC), an aggressive and highly metastatic subtype of breast cancer. Glioma-associated oncogene 1 (GLI1) is a transcription factor and effector of the Hedgehog (Hh) signaling pathway, and is predictive of poor survival for TNBC patients. A nanostring DNA Damage Response (DDR) mRNA panel was used to identify GLI1-induced regulation of DDR genes. Western blots, immunohistochemistry and immunofluorescence were used to evaluate protein expression. Colony assays and mammosphere formation assays were utilized to assess survival of cancer cells. Flow cytometry analyses were employed to evaluate changes in the cell cycle profile, and DNA fiber assays were used to analyze alterations in replication dynamics in TNBC cells. The UALCAN portal and Ensemble programs were used for computational analysis of TCGA data. CompuSyn software was used to calculate combination index (CI) values to assess synergism in drug combination experiments. Inhibition of GLI1 in TNBC cells transcriptionally downregulate expression of FANCD2 and its foci formation, and causes a homologous recombination repair (HR) deficiency. As HR-deficient cancer cells are sensitive to PARP-targeted therapies, we evaluated a combination of the GLI1 inhibitor, GANT61, and a PARP inhibitor (olaparib) in TNBC cells. Combination of GANT61 and olaparib elevated DNA damage levels and these drug combinations caused synergistic lethality to TNBC cells. Aberrantly activated GLI1 regulates HR-mediated DNA repair by transcriptionally regulating FANCD2 to overcome chemotherapy-induced replication stress and DNA damage, and it contributes to resistance of TNBC cells to therapeutics.
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Affiliation(s)
- Chinnadurai Mani
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Kaushlendra Tripathi
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36904, USA
| | - Tasmin R Omy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Mark Reedy
- Department of Obstetrics and Gynecology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Komaraiah Palle
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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Qiu S, Zhou Y, Kim JT, Bao C, Lee HJ, Chen J. Amentoflavone inhibits tumor necrosis factor-α-induced migration and invasion through AKT/mTOR/S6k1/hedgehog signaling in human breast cancer. Food Funct 2021; 12:10196-10209. [PMID: 34542136 DOI: 10.1039/d1fo01085a] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Inflammatory cytokine tumor necrosis factor-α (TNFα) has been demonstrated to accelerate the progression and metastasis of various carcinomas. In this study, we investigated the effect of amentoflavone on inhibiting the migration and invasion of TNFα-induced breast cancer cells. Results showed that amentoflavone significantly blocked the cellular migration and invasion of MCF10DCIS.com and MDA-MB-231 cells at a concentration of 10 μM but did not affect the cell viability. The mRNA and protein levels of matrix metalloproteinase (MMP)-9, significantly activated by TNFα, were reversed by amentoflavone treatment in a dose-dependent manner in MCF10DCIS.com cells. Congruent with the protein level, the activity of MMP-9 was significantly suppressed by amentoflavone treatment. Additionally, we found that amentoflavone dampened Gli1-dependent noncanonical hedgehog signaling, which is a key factor in the regulation of migration and invasion in TNFα-induced human breast cancer cells. Further study elucidated that TNFα enhanced Gli1 through the activation of the AKT/mTOR/S6K1 cascade, whereas it receded after amentoflavone treatment in human breast cancer cells. In summary, amentoflavone abrogated Gli1 activation in TNFα-induced mammary tumor cells, resulting in a decrease of invasiveness in human breast cancer cells via mediating AKT/mTOR/S6K1 signaling. Amentoflavone should be considered as a potent food ingredient for the retardation of mammary tumorigenesis.
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Affiliation(s)
- Shuai Qiu
- Department of Food Science and Technology, Chung-Ang University, Anseong, 17546, South Korea.
| | - Yimeng Zhou
- Department of Food Science and Technology, Chung-Ang University, Anseong, 17546, South Korea.
| | - Jin Tae Kim
- Department of Food Science and Technology, Chung-Ang University, Anseong, 17546, South Korea.
| | - Cheng Bao
- School of Life Science, Ludong University, Yantai, 264025, China
| | - Hong Jin Lee
- Department of Food Science and Technology, Chung-Ang University, Anseong, 17546, South Korea.
| | - Jing Chen
- Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, 510632, China.
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Ko YC, Choi HS, Liu R, Lee DS. Physalin A, 13,14-Seco-16, 24-Cyclo-Steroid, Inhibits Stemness of Breast Cancer Cells by Regulation of Hedgehog Signaling Pathway and Yes-Associated Protein 1 (YAP1). Int J Mol Sci 2021; 22:ijms22168718. [PMID: 34445421 PMCID: PMC8395918 DOI: 10.3390/ijms22168718] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 12/25/2022] Open
Abstract
The Hedgehog (HH) signaling pathway plays an important role in embryonic development and adult organ homeostasis. Aberrant activity of the Hedgehog signaling pathway induces many developmental disorders and cancers. Recent studies have investigated the relationship of this pathway with various cancers. GPCR-like protein Smoothened (SMO) and the glioma-associated oncogene (GLI1) are the main effectors of Hedgehog signaling. Physalin A, a bioactive substance derived from Physalis alkekengi, inhibits proliferation and migration of breast cancer cells and mammospheres formation. Physalin A-induced apoptosis and growth inhibition of mammospheres, and reduced transcripts of cancer stem cell (CSC) marker genes. Physalin A reduced protein expressions of SMO and GLI1/2. Down-regulation of SMO and GLI1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation by reducing GLI1 gene expression. Down-regulation of GLI1 reduced CSC marker genes. Physalin A reduced protein level of YAP1. Down-regulation of YAP1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation through reduction of YAP1 gene expression. Down-regulation of YAP1 reduced CSC marker genes. We showed that treatment of MDA-MB-231 breast cancer cells with GLI1 siRNA induced inhibition of mammosphere formation and down-regulation of YAP1, a Hippo pathway effector. These results show that Hippo signaling is regulated by the Hedgehog signaling pathway. Physalin A also inhibits the canonical Hedgehog and Hippo signaling pathways, CSC-specific genes, and the formation of mammospheres. These findings suggest that physalin A is a potential therapeutic agent for targeting CSCs.
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Affiliation(s)
- Yu-Chan Ko
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea; (Y.-C.K.); (R.L.)
| | - Hack Sun Choi
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea;
- Bio-Health Materials Core-Facility Center, Jeju National University, Jeju 63243, Korea
| | - Ren Liu
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea; (Y.-C.K.); (R.L.)
| | - Dong-Sun Lee
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju 63243, Korea; (Y.-C.K.); (R.L.)
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea;
- Bio-Health Materials Core-Facility Center, Jeju National University, Jeju 63243, Korea
- Practical Translational Research Center, Jeju National University, Jeju 63243, Korea
- Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju 63243, Korea
- Correspondence:
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Qayoom H, Wani NA, Alshehri B, Mir MA. An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer. Future Oncol 2021; 17:4185-4206. [PMID: 34342489 DOI: 10.2217/fon-2021-0172] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the most complex, aggressive and fatal subtype of breast cancer. Owing to the lack of targeted therapy and heterogenic nature of TNBC, chemotherapy remains the sole treatment option for TNBC, with taxanes and anthracyclines representing the general chemotherapeutic regimen in TNBC therapy. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. Breast cancer stem cells (BCSCs) are one of the major causes for the development of chemoresistance in TNBC patients. After surviving the chemotherapy damage, the presence of BCSCs results in relapse and recurrence of TNBC. Several pathways are known to regulate BCSCs' survival, such as the Wnt/β-catenin, Hedgehog, JAK/STAT and HIPPO pathways. Therefore it is imperative to target these pathways in the context of eliminating chemoresistance. In this review we will discuss the novel strategies and various preclinical and clinical studies to give an insight into overcoming TNBC chemoresistance. We present a detailed account of recent studies carried out that open an exciting perspective in relation to the mechanisms of chemoresistance.
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Affiliation(s)
- Hina Qayoom
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, J&K, India
| | - Nissar A Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir Nunar Ganderbal 191201, J&K, India
| | - Bader Alshehri
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, KSA
| | - Manzoor A Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, J&K, India
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Differential Expression of BOC, SPOCK2, and GJD3 Is Associated with Brain Metastasis of ER-Negative Breast Cancers. Cancers (Basel) 2021; 13:cancers13122982. [PMID: 34203581 PMCID: PMC8232218 DOI: 10.3390/cancers13122982] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 01/05/2023] Open
Abstract
Simple Summary Brain metastasis is diagnosed in 30–50% of metastatic breast cancer patients with currently limited treatment strategies and usually short survival rates. In the present study, we aim to identify genes specifically associated with the development of brain metastasis in breast cancer. Therefore, we compared RNA expression profiles from two groups of patients with metastatic breast cancer, with and without brain involvement. Three genes BOC, SPOCK2, and GJD3 were overexpressed in the group of primary breast cancers which developed brain metastasis. Expression profiles were confirmed in an independent breast cancer cohort for both BOC and SPOCK2. In addition, differential overexpression of SPOCK2 and GJD3 mRNA levels were found to be associated with the development of brain metastasis in an external online database of 204 primary breast cancers. Verification of these genes as biomarkers for brain metastasis development in primary breast cancer is warranted. Abstract Background: Brain metastasis is considered one of the major causes of mortality in breast cancer patients. To invade the brain, tumor cells need to pass the blood-brain barrier by mechanisms that are partially understood. In primary ER-negative breast cancers that developed brain metastases, we found that some of the differentially expressed genes play roles in the T cell response. The present study aimed to identify genes involved in the formation of brain metastasis independently from the T cell response. Method: Previously profiled primary breast cancer samples were reanalyzed. Genes that were found to be differentially expressed were confirmed by RT-PCR and by immunohistochemistry using an independent cohort of samples. Results: BOC, SPOCK2, and GJD3 were overexpressed in the primary breast tumors that developed brain metastasis. BOC expression was successfully validated at the protein level. SPOCK2 was validated at both mRNA and protein levels. SPOCK2 and GJD3 mRNA overexpression were also found to be associated with cerebral metastasis in an external online database consisting of 204 primary breast cancers. Conclusion: The overexpression of BOC, SPOCK2, and GJD3 is associated with the invasion of breast cancer into the brain. Further studies to determine their specific function and potential value as brain metastasis biomarkers are required.
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García-Martínez A, Pérez-Balaguer A, Ortiz-Martínez F, Pomares-Navarro E, Sanmartín E, García-Escolano M, Montoyo-Pujol YG, Castellón-Molla E, Peiró G. Hedgehog gene expression patterns among intrinsic subtypes of breast cancer: Prognostic relevance. Pathol Res Pract 2021; 223:153478. [PMID: 34022683 DOI: 10.1016/j.prp.2021.153478] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Hedgehog (Hh) signaling is a crucial developmental regulatory pathway recognized as a primary oncogenesis driver in various human cancers. However, its role in breast carcinoma (BC) has been underexplored. METHODS We analyzed the expression of several Hh associated genes in a clinical series and breast cancer cell lines. We included 193 BC stratified according to intrinsic immunophenotypes. Gene expression profiling ofBOC, PTCH, SMO, GLI1, GLI2, and GLI3 was performed by qRT-PCR. Results were correlated with clinical-pathological variables and outcome. RESULTS We observed expression ofGLI2 in triple-negative/basal-like (TN/BL) and GLI3 in luminal cells. In samples, BOC, GLI1, GLI2, and GLI3 expression correlated significantly with luminal tumors and good prognostic factors. In contrast, PTCH and SMO correlated with TN/BL phenotype and nodal involvement. Patients whose tumors expressed SMO had a poorer outcome, especially those with HER2 phenotype. Positive lymph-node status and high SMO remained independent poor prognostic factors. CONCLUSION Our results support a differential Hh pathway activation in BC phenotypes.SMO levels stratified patients at risk of recurrence and death in HER2 phenotype, and it showed an independent prognostic value. Therefore, SMO could be a potential therapeutic target for a subset of BC patients.
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Affiliation(s)
- Araceli García-Martínez
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain.
| | - Ariadna Pérez-Balaguer
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Fernando Ortiz-Martínez
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Eloy Pomares-Navarro
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Elena Sanmartín
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Marta García-Escolano
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Yoel G Montoyo-Pujol
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Elena Castellón-Molla
- Pathology Dept., University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Gloria Peiró
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain; Pathology Dept., University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
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15
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Zhong J, Shan W, Zuo Z. Norepinephrine inhibits migration and invasion of human glioblastoma cell cultures possibly via MMP-11 inhibition. Brain Res 2021; 1756:147280. [PMID: 33515535 DOI: 10.1016/j.brainres.2021.147280] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/31/2020] [Accepted: 01/06/2021] [Indexed: 12/14/2022]
Abstract
PURPOSE Growing evidence has shown that the stress hormones affect tumor progression. Patients with surgery to remove tumor often have increased norepinephrine during the perioperative period. However, the effect of norepinephrine on the progression of glioblastoma has not yet studied. Therefore, the present study aimed at investigating the effects of norepinephrine on the migration and invasion of the human glioblastoma U87 and U251 cell lines and the mechanism for the effects. METHODS The U87 and U251 cells were treated with 0, 0.1, 1, 5, 10 or 50 μM norepinephrine. A scratch wound healing assay and a transwell invasion assay were used to investigate cell migration and invasion, respectively. The Human Tumor Metastasis RT2 Profiler PCR Array was used to detect the expression of 84 genes known to be involved in metastasis. RESULTS Following norepinephrine treatment, the ability of the U87 and U251 cells to migrate and invade was significantly decreased. Human Tumor Metastasis RT2 Profiler PCR Array assay showed that matrix metallopeptidase-11 (MMP-11) was decreased following norepinephrine treatment. The β-adrenergic receptor blocker (AR) propranolol blunted the suppressive effect of norepinephrine on the migration and invasion of U251 cells but did not have such an effect on the invasion of U87 cells. MMP-11 silencing inhibited the migration and invasion of U87 and U251 cells. The Cancer Genome Atlas data showed that patients with higher expression of MMP-11 in the glioblastoma tissues had poorer prognosis. CONCLUSION Our results indicate that norepinephrine inhibits the migration and invasion of human glioblastoma cells. This effect may be mediated by the decrease of MMP-11. β-AR may be a regulatory factor for this effect in U251 cells.
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Affiliation(s)
- Jing Zhong
- Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA; Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weiran Shan
- Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA
| | - Zhiyi Zuo
- Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA.
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Kuehn J, Espinoza-Sanchez NA, Teixeira FCOB, Pavão MSG, Kiesel L, Győrffy B, Greve B, Götte M. Prognostic significance of hedgehog signaling network-related gene expression in breast cancer patients. J Cell Biochem 2021; 122:577-597. [PMID: 33417295 DOI: 10.1002/jcb.29886] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 12/25/2022]
Abstract
Breast cancer continues to be a serious public health problem. The role of the hedgehog pathway in normal development of the mammary gland as well as in carcinogenesis and progression of breast cancer is the subject of intense investigation, revealing functional interactions with cell surface heparan sulfate. Nevertheless, its influence on breast cancer prognosis, and its relation to specific sulfation motifs in heparan sulfate have only been poorly studied in large patient cohorts. Using the public database KMplotter that includes gene expression and survival data of 3951 patients, we found that the higher expression of SHH, HHAT, PTCH1, GLI1, GLI2, and GLI3 positively influences breast cancer prognosis. Stratifying patients according to the expression of hormone receptors, histological grade, lymph node metastasis, and systemic therapy, we observed that GLI1, GLI2, and GLI3 expression, as well as co-expression of SHH and ELP1 were associated with worse relapse-free survival in patients with HER2-positive tumors. Moreover, GLI1 expression in progesterone receptor-negative tumors and GLI3 expression in grade 3 tumors correlated with poor prognosis. SHH, in a panel of cell lines representing different breast cancer subtypes, and HHAT, PTCH1, GLI1, GLI2, and GLI3 were mostly expressed in cell lines classified as HER2-positive and basal-like. Expression of SHH, HHAT, GLI2, and GLI3 was differentially affected by overexpression of the heparan sulfate sulfotransferases HS2ST1 and HS3ST2 in vitro. Although high HS2ST1 expression was associated with poor prognosis in KMplotter analysis, high levels of HS3ST2 were associated with a good prognosis, except for ER-positive breast cancer. We suggest the GLI transcription factors as possible markers for the diagnosis, treatment, and prognosis of breast cancer especially in HER2-positive tumors, but also in progesterone receptor-negative and grade-3 tumors. The pathway interaction and prognostic impact of specific heparan sulfate sulfotransferases provide novel perspectives regarding a therapeutical targeting of the hedgehog pathway in breast cancer.
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Affiliation(s)
- Julia Kuehn
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
| | - Nancy Adriana Espinoza-Sanchez
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.,Department of Radiotherapy-Radiooncology, Münster University Hospital, Münster, Germany
| | - Felipe C O B Teixeira
- Instituto de Bioquímica Médica Leopoldo de Meis, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mauro S G Pavão
- Instituto de Bioquímica Médica Leopoldo de Meis, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ludwig Kiesel
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, and Semmelweis University 2nd Department of Pediatrics, TTK Momentum Cancer Biomarker Research Group, Budapest, Hungary
| | - Burkhard Greve
- Department of Radiotherapy-Radiooncology, Münster University Hospital, Münster, Germany
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
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Nutini A, Sohail A. Deep learning of the role of interleukin IL-17 and its action in promoting cancer. BIO-ALGORITHMS AND MED-SYSTEMS 2020; 16. [DOI: 10.1515/bams-2020-0052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Abstract
In breast cancer patients, metastasis remains a major cause of death. The metastasis formation process is given by an interaction between the cancer cells and the microenvironment that surrounds them. In this article, we develop a mathematical model that analyzes the role of interleukin IL-17 and its action in promoting cancer and in facilitating tissue metastasis in breast cancer, using a dynamic analysis based on a stochastic process that accounts for the local and global action of this molecule. The model uses the Ornstein–Uhlembeck and Markov process in continuous time. It focuses on the oncological expansion and the interaction between the interleukin IL-17 and cell populations This analysis tends to clarify the processes underlying the metastasis expansion mechanism both for a better understanding of the pathological event and for a possible better control of therapeutic strategies.
IL-17 is a proinflammatory interleukin that acts when there is tissue damage or when there is a pathological situation caused by an external pathogen or by a pathological condition such as cancer.
This research is focused on the role of interleukin IL-17 which, especially in the case of breast cancer, turns out to be a dominant “communication pin” since it interconnects with the activity of different cell populations affected by the oncological phenomenon. Stochastic modeling strategies, specially the Ornstein-Uhlenbeck process, with the aid of numerical algorithms are elaborated in this review.
The role of IL-17 is discussed in this manuscript at all the stages of cancer. It is discussed that IL-17 also acts as “metastasis promoter” as a result of its proinflammatory nature. The stochastic nature of IL-17 is discussed based on the evidence provided by recent literature.
The resulting dynamical analysis can help to select the most appropriate therapeutic strategy.
Cancer cells, in the case of breast cancer, have high level of IL-17 receptors (IL-17R); therefore the interleukin itself has direct effects on these cells. Immunotherapy research, focused on this cytokine and interlinked with the stochastic modeling, seems to be a promising avenue.
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Affiliation(s)
- Alessandro Nutini
- Center for Study in Motor Science , Biomechanics dept , Lucca , Italy
| | - Ayesha Sohail
- Department of Mathematics , Comsats University Islamabad , Lahore 54000 , Pakistan
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18
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The Role of Smoothened in Cancer. Int J Mol Sci 2020; 21:ijms21186863. [PMID: 32962123 PMCID: PMC7555769 DOI: 10.3390/ijms21186863] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/13/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023] Open
Abstract
Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.
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19
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Kong D, Hughes CJ, Ford HL. Cellular Plasticity in Breast Cancer Progression and Therapy. Front Mol Biosci 2020; 7:72. [PMID: 32391382 PMCID: PMC7194153 DOI: 10.3389/fmolb.2020.00072] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/31/2020] [Indexed: 12/24/2022] Open
Abstract
With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.
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Affiliation(s)
- Deguang Kong
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Connor J. Hughes
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Heide L. Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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20
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Miguel AFP, Mello FW, Melo G, Rivero ERC. Association between immunohistochemical expression of matrix metalloproteinases and metastasis in oral squamous cell carcinoma: Systematic review and meta-analysis. Head Neck 2020; 42:569-584. [PMID: 31750584 DOI: 10.1002/hed.26009] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 10/09/2019] [Accepted: 10/30/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The aim of this systematic review (SR) was to summarize and critically appraise available evidence on the association of the immunohistochemical expression of matrix metalloproteinases (MMPs) with the occurrence of lymph node/distant metastasis of oral squamous cell carcinoma (OSCC). METHODS Searches were conducted in five main electronic and three gray literature databases. RESULTS From 2128 records identified, 50 were included for qualitative analysis. A total of 12 MMPs were identified (-1, -2, -3, -7, -8, -9, -10, -11, -13, -25, -26, and MT1-MMP). Most included studies reported a positive association of MMP-1, -2, -3, -7, -9, and MT1-MMP with lymph node metastasis. MMP-8, -25, and -26 were not associated with lymph node metastasis. CONCLUSIONS According to this SR, MMP-1, -2, -3, -7, -9, and MT1-MMP seem to play an important role in lymph node metastasis of OSCC.
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Affiliation(s)
- Andressa F P Miguel
- Postgraduate Program in Dentistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Fernanda W Mello
- Postgraduate Program in Dentistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Gilberto Melo
- Postgraduate Program in Dentistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Elena R C Rivero
- Department of Pathology, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
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21
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Jeng KS, Chang CF, Lin SS. Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments. Int J Mol Sci 2020; 21:ijms21030758. [PMID: 31979397 PMCID: PMC7037908 DOI: 10.3390/ijms21030758] [Citation(s) in RCA: 140] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/20/2020] [Accepted: 01/20/2020] [Indexed: 02/07/2023] Open
Abstract
During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.
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22
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Pyczek J, Khizanishvili N, Kuzyakova M, Zabel S, Bauer J, Nitzki F, Emmert S, Schön MP, Boukamp P, Schildhaus HU, Uhmann A, Hahn H. Regulation and Role of GLI1 in Cutaneous Squamous Cell Carcinoma Pathogenesis. Front Genet 2019; 10:1185. [PMID: 31867038 PMCID: PMC6904360 DOI: 10.3389/fgene.2019.01185] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 10/25/2019] [Indexed: 02/03/2023] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin tumor in humans. Although current therapies are sufficient to clear the tumor in many cases, the overall risk of cSCC metastasis is still 5%. Alternative treatment options could help to overcome this situation. Here we focused on the role of the Hedgehog (HH) signaling pathway and its interplay with epidermal growth factor receptor (EGFR) signaling in cSCC. The analyses revealed that, despite lack of Sonic HH (SHH) expression, a subset of human cSCC can express GLI1, a marker for active HH signaling, within distinct tumor areas. In contrast, all tumors strongly express EGFR and the hair follicle stem cell marker SOX9 at the highly proliferative tumor-stroma interface, whereas central tumor regions with a more differentiated stratum spinosum cell type lack both EGFR and SOX9 expression. In vitro experiments indicate that activation of EGFR signaling in the human cSCC cell lines SCL-1, MET-1, and MET-4 leads to GLI1 inhibition via the MEK/ERK axis without affecting cellular proliferation. Of note, EGFR activation also inhibits cellular migration of SCL-1 and MET-4 cells. Because proliferation and migration of the cells is also not altered by a GLI1 knockdown, GLI1 is apparently not involved in processes of aggressiveness in established cSCC tumors. In contrast, our data rather suggest a negative correlation between Gli1 expression level and cSCC formation because skin of Ptch+/- mice with slightly elevated Gli1 expression levels is significantly less susceptible to chemically-induced cSCC formation compared to murine wildtype skin. Although not yet formally validated, these data open the possibility that GLI1 (and thus HH signaling) may antagonize cSCC initiation and is not involved in cSCC aggressiveness, at least in a subset of cSCC.
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Affiliation(s)
- Joanna Pyczek
- Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany
| | - Natalia Khizanishvili
- Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany
| | - Maria Kuzyakova
- Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany
| | - Sebastian Zabel
- Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany
| | - Julia Bauer
- Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany
| | - Frauke Nitzki
- Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany
| | - Steffen Emmert
- Department of Dermatology and Venerology, University Medical Center Rostock, Rostock, Germany
| | - Michael P Schön
- Department of Dermatology, Venerology and Allergology, University Medical Center Goettingen, Goettingen, Germany
| | - Petra Boukamp
- Division of Genetics of Skin Carcinogenesis, German Cancer Research Center (DKFZ) Heidelberg, Germany
| | | | - Anja Uhmann
- Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany
| | - Heidi Hahn
- Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany
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Xu Y, Song S, Wang Z, Ajani JA. The role of hedgehog signaling in gastric cancer: molecular mechanisms, clinical potential, and perspective. Cell Commun Signal 2019; 17:157. [PMID: 31775795 PMCID: PMC6882007 DOI: 10.1186/s12964-019-0479-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023] Open
Abstract
Patients with advanced gastric cancer usually have a poor prognosis and limited therapeutic options. Overcoming this challenge requires novel targets and effective drugs. The Hedgehog (Hh) signaling pathway plays a crucial role in the development of the gastrointestinal tract and maintenance of the physiologic function of the stomach. Aberrantly activated Hh signaling is implicated in carcinogenesis as well as maintenance of cancer stem cells. Somatic mutations in the components of Hh signaling (PTCH1 and SMO) have been shown to be a major cause of basal cell carcinoma, and dozens of Hh inhibitors have been developed. To date, two inhibitors (GDC-0449 and LDE225) have been approved by the U.S. Food and Drug Administration to treat basal cell carcinoma and medulloblastoma. Here, we review the role of the Hh signaling in the carcinogenesis and progression of gastric cancer and summarize recent findings on Hh inhibitors in gastric cancer. Hedgehog signaling is often aberrantly activated and plays an important role during inflammation and carcinogenesis of gastric epithelial cells. Further study of the precise mechanisms of Hh signaling in this disease is needed for the validation of therapeutic targets and evaluation of the clinical utility of Hh inhibitors for gastric cancer.
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Affiliation(s)
- Yan Xu
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.,Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China.
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.
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Al-Jawadi A, Rasha F, Ramalingam L, Alhaj S, Moussa H, Gollahon L, Dharmawardhane S, Moustaid-Moussa N. Protective effects of eicosapentaenoic acid in adipocyte-breast cancer cell cross talk. J Nutr Biochem 2019; 75:108244. [PMID: 31704550 DOI: 10.1016/j.jnutbio.2019.108244] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 08/23/2019] [Accepted: 09/10/2019] [Indexed: 10/25/2022]
Abstract
Breast cancer is the leading cause of death in women among all cancer types. Obesity is one of the factors that promote progression of breast cancer, especially in post-menopausal women. Increasingly, adipose tissue is recognized for its active role in the tumor microenvironment. We hypothesized that adipocytes conditioned medium can impact breast cancer progression by increasing inflammatory cytokines production by cancer cells, and subsequently increasing their motility. By contrast, eicosapentaenoic acid (EPA), an anti-inflammatory n-3 polyunsaturated fatty acid, reduces adipocyte-secreted inflammatory factors, leading to reduced cancer cell motility. To test these hypotheses, we investigated the direct effects of EPA on MCF-7 and MDA-MB-231 breast cancer cells and the effects of conditioned medium from 3 T3-L1 or human mesenchymal stem cells (HMSC)-derived adipocytes treated with or without EPA supplementation on breast cancer cells. We observed that conditioned medium from HMSC-derived adipocytes significantly increased mRNA transcription levels of cancer-associated genes such as FASN, STAT3 and cIAP2, while EPA-treated HMSC-derived adipocytes significantly reduced mRNA levels of these genes. However, direct EPA treatment significantly reduced mRNA content of these tumor-associated markers (FASN, STAT3, cIAP-2) only in MDA-MB-231 cells not in MCF-7 cells. Conditioned medium from EPA-treated 3 T3-L1 adipocytes further decreased inflammation, cell motility and glycolysis in cancer cells. Our data confirms that adipocytes play a significant role in promoting breast cancer progression and demonstrates that EPA-treated adipocytes reduced the negative impact of adipocyte-secreted factors on breast cancer cell inflammation and migration.
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Affiliation(s)
- Arwa Al-Jawadi
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron ave, Lubbock, TX 79409, USA
| | - Fahmida Rasha
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron ave, Lubbock, TX 79409, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX 794909, USA
| | - Latha Ramalingam
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron ave, Lubbock, TX 79409, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX 794909, USA
| | - Sara Alhaj
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron ave, Lubbock, TX 79409, USA
| | - Hanna Moussa
- Obesity Research Institute, Texas Tech University, Lubbock, TX 794909, USA; Department of Mechanical Engineering; Texas Tech University, Lubbock, TX 79409, USA
| | - Lauren Gollahon
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron ave, Lubbock, TX 79409, USA; Department of Biological Sciences, Texas Tech University, 2901 Main st, Lubbock, TX 79409, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX 794909, USA
| | - Suranganie Dharmawardhane
- Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, Texas Tech University, 1301 Akron ave, Lubbock, TX 79409, USA; Obesity Research Institute, Texas Tech University, Lubbock, TX 794909, USA.
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25
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Yang H, Jiang P, Liu D, Wang HQ, Deng Q, Niu X, Lu L, Dai H, Wang H, Yang W. Matrix Metalloproteinase 11 Is a Potential Therapeutic Target in Lung Adenocarcinoma. Mol Ther Oncolytics 2019; 14:82-93. [PMID: 31024988 PMCID: PMC6477516 DOI: 10.1016/j.omto.2019.03.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 03/27/2019] [Indexed: 12/29/2022] Open
Abstract
Lung cancer is one of the leading causes of cancer-associated death, with the etiology largely unknown. The aim of this study was to identify key driver genes with therapeutic potentials in lung adenocarcinoma (LUAD). Transcriptome microarray data from four GEO datasets (GEO: GSE7670, GSE10072, GSE68465, and GSE43458) were jointly analyzed for differentially expressed genes (DEGs). Ontologic analysis showed that most of the upregulated DEGs enriched in collagen catabolic and fibril organization processes were regulated by matrix metalloproteinases (MMPs). Matrix metalloproteinase 11 (MMP11), the highest upregulated MMP family member in LUAD-transformed cells, acted in an autocrine manner and was significantly increased in sera of LUAD patients. MMP11 depletion severely impaired LUAD cell proliferation, migration, and invasion in vitro, in line with retarded tumor growth in xenograft models. Treatment of different human LUAD cell lines with anti-MMP11 antibody significantly retarded cell growth and migration. Administration of anti-MMP11 antibody at a dose of 1 μg/g body weight significantly suppressed tumor growth in xenograft models. These findings indicate that MMP11 is a key cancer driver gene in LUAD and is an appealing target for antibody therapy.
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Affiliation(s)
- Haoran Yang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- University of Science and Technology of China, Hefei 230026, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Peng Jiang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- University of Science and Technology of China, Hefei 230026, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Dongyan Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- University of Science and Technology of China, Hefei 230026, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Hong-Qiang Wang
- Biological Molecular Information System Lab., Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Qingmei Deng
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Xiaojie Niu
- Department of Anatomy, Shanxi Medical University, Taiyuan 030024, China
| | - Li Lu
- Department of Anatomy, Shanxi Medical University, Taiyuan 030024, China
| | - Haiming Dai
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Hongzhi Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Wulin Yang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
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26
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Nedeljković M, Damjanović A. Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer-How We Can Rise to the Challenge. Cells 2019; 8:E957. [PMID: 31443516 PMCID: PMC6770896 DOI: 10.3390/cells8090957] [Citation(s) in RCA: 523] [Impact Index Per Article: 87.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 08/21/2019] [Indexed: 02/07/2023] Open
Abstract
Triple-negative (TNBC) is the most lethal subtype of breast cancer owing to high heterogeneity, aggressive nature, and lack of treatment options. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance. Accordingly, in recent years, tremendous effort has been made into elucidating the mechanisms of TNBC chemoresistance with the goal of identifying new molecular targets. It has become evident that the development of TNBC chemoresistance is multifaceted and based on the elaborate interplay of the tumor microenvironment, drug efflux, cancer stem cells, and bulk tumor cells. Alterations of multiple signaling pathways govern these interactions. Moreover, TNBC's high heterogeneity, highlighted in the existence of several molecular signatures, presents a significant obstacle to successful treatment. In the present, in-depth review, we explore the contribution of key mechanisms to TNBC chemoresistance as well as emerging strategies to overcome them. We discuss novel anti-tumor agents that target the components of these mechanisms and pay special attention to their current clinical development while emphasizing the challenges still ahead of successful TNBC management. The evidence presented in this review outlines the role of crucial pathways in TNBC survival following chemotherapy treatment and highlights the importance of using combinatorial drug strategies and incorporating biomarkers in clinical studies.
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Affiliation(s)
- Milica Nedeljković
- Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
| | - Ana Damjanović
- Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
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27
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Bhateja P, Cherian M, Majumder S, Ramaswamy B. The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer? Cancers (Basel) 2019; 11:cancers11081126. [PMID: 31394751 PMCID: PMC6721501 DOI: 10.3390/cancers11081126] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/23/2019] [Accepted: 07/30/2019] [Indexed: 12/24/2022] Open
Abstract
The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. Deregulation of the Hh pathway is a key driver of basal cell carcinoma, and therapeutic targeting led to approval of Hh inhibitor, vismodegib, in the management of this cancer. The Hh pathway is implicated in other malignancies including hormone receptor (HR+) positive and triple negative breast cancer (TNBC). Hh signaling, which is activated in human mammary stem cells, results in activation of glioma-associated oncogene (GLI) transcription factors. High GLI1 expression correlates with worse outcomes in breast cancer. Non-canonical GLI1 activation is one mechanism by which estrogen exposure promotes breast cancer stem cell proliferation and epithelial–mesenchymal transition. Tamoxifen resistant cell lines show aberrant activation of Hh signaling, and knockdown of Hh pathway inhibited growth of tamoxifen resistant cells. As in other cancers Hh signaling is activated by the PI3K/AKT pathway in these endocrine resistant cell lines. Hh pathway activation has also been reported to mediate chemotherapy resistance in TNBC via various mechanisms including paracrine signaling to tumor micro-environment and selective proliferation of cancer stem cells. Co-activation of Hh and Wnt signaling pathways is a poor prognostic marker in TNBC. Early phase clinical trials are evaluating the combination of smoothened (SMO) inhibitors and chemotherapy in TNBC. In addition to SMO inhibitors like vismodegib and sonidegib, which are in clinical use for basal cell carcinoma, GLI1 inhibitors like GANT58 and GANT61 are in preclinical drug development and might be an effective mechanism to overcome drug resistance in breast cancer. Gene signatures predictive of Hh pathway activation could enrich for patients likely to respond to these agents.
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Affiliation(s)
- Priyanka Bhateja
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Mathew Cherian
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Sarmila Majumder
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Bhuvaneswari Ramaswamy
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
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28
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Xia H, Yu W, Liu M, Li H, Pang W, Wang L, Zhang Y. An integrated bioinformatics analysis of potential therapeutic targets among matrix metalloproteinases in breast cancer. Oncol Lett 2019; 18:2985-2994. [PMID: 31452777 PMCID: PMC6704324 DOI: 10.3892/ol.2019.10669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 06/14/2019] [Indexed: 12/24/2022] Open
Abstract
Breast cancer (BC) is one of the most aggressive malignancies worldwide among females. Matrix metalloproteinases (MMPs), as the most abundant class of non-serine proteases present in invasive and metastatic tumors, can regulate a variety of alterations in the microenvironment during tumor progression. However, the differential expression of MMPs and its prognostic values in BC is yet to be elucidated. In this research, using the ONCOMINE dataset, The Cancer Genome Atlas, Breast Cancer Gene-Expression Miner v4.1 (Bc-GenExMiner), Kaplan-Meier Plotter and cBioPortal, the transcriptional MMPs and survival outcome data of patients with BC was compared. It was indicated that mRNA levels of MMP1/3/9/10/11/12/13 were increased compared with non-tumor tissues, whereas mRNA expression of MMP2/16/19/23B/28 was lower in BC tissues. Kaplan-Meier plots showed that high mRNA levels of MMP2/10/16/19/20/23B/27 in patients with BC were associated with better recurrence-free survival. In contrast, high MMP1/8/9/11/12 conferred worse RFS rate. Meanwhile, high transcription levels of MMP1/3/11/12/13 predicted shorter distant metastasis-free survival, while high levels of MMP1/12 demonstrated worse overall survival in patients with BC. From Bc-GenExMiner, it was indicated that high expression of MMP16/20 was correlated with better prognosis, while MMP1/9/11/12/13/14/15 exerted a negative effect on patient prognosis. The integrative bioinformatics analysis performed in the present study suggests that MMP1/9/12/16, compared with other MMPs, are potentially appropriate targets for targeted therapy in patients with BC.
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Affiliation(s)
- Haiqun Xia
- Department of Radiation Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong 523000, P.R. China
| | - Weixuan Yu
- Department of Surgical Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong 523000, P.R. China
| | - Ming Liu
- Department of Surgical Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong 523000, P.R. China
| | - Hong Li
- Department of Surgical Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong 523000, P.R. China
| | - Wei Pang
- Department of Radiation Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong 523000, P.R. China
| | - Libin Wang
- Department of Surgical Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong 523000, P.R. China
| | - Yunda Zhang
- Department of Surgical Oncology, Tungwah Hospital of Sun Yat-Sen University, Dongguan, Guangdong 523000, P.R. China
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29
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Role of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics. Cells 2019; 8:cells8040375. [PMID: 31027259 PMCID: PMC6523618 DOI: 10.3390/cells8040375] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 04/22/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
Breast cancer (BC) is the leading cause of cancer-related mortality in women, only followed by lung cancer. Given the importance of BC in public health, it is essential to identify biomarkers to predict prognosis, predetermine drug resistance and provide treatment guidelines that include personalized targeted therapies. The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, tissue regeneration, and stem cell renewal. Several lines of evidence endorse the important role of canonical and non-canonical Hh signaling in BC. In this comprehensive review we discuss the role of Hh signaling in breast development and homeostasis and its contribution to tumorigenesis and progression of different subtypes of BC. We also examine the efficacy of agents targeting different components of the Hh pathway both in preclinical models and in clinical trials. The contribution of the Hh pathway in BC tumorigenesis and progression, its prognostic role, and its value as a therapeutic target vary according to the molecular, clinical, and histopathological characteristics of the BC patients. The evidence presented here highlights the relevance of the Hh signaling in BC, and suggest that this pathway is key for BC progression and metastasis.
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30
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Javadian M, Gharibi T, Shekari N, Abdollahpour‐Alitappeh M, Mohammadi A, Hossieni A, Mohammadi H, Kazemi T. The role of microRNAs regulating the expression of matrix metalloproteinases (MMPs) in breast cancer development, progression, and metastasis. J Cell Physiol 2018; 234:5399-5412. [DOI: 10.1002/jcp.27445] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Mahsa Javadian
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
- Student Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Najibeh Shekari
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | | | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Arezoo Hossieni
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Hamed Mohammadi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
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31
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Qin X, Zhao H, Jiang Y, Yin F, Tian Y, Xie M, Ye X, Xu N, Li Z. Development of a potent peptide inhibitor of estrogen receptor α. CHINESE CHEM LETT 2018. [DOI: 10.1016/j.cclet.2018.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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32
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Chalakur-Ramireddy NKR, Pakala SB. Combined drug therapeutic strategies for the effective treatment of Triple Negative Breast Cancer. Biosci Rep 2018; 38:BSR20171357. [PMID: 29298879 PMCID: PMC5789156 DOI: 10.1042/bsr20171357] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 12/12/2017] [Accepted: 01/01/2018] [Indexed: 12/19/2022] Open
Abstract
TNBC (Triple Negative Breast Cancer) is a subtype of breast cancer with an aggressive phenotype which shows high metastatic capability and poor prognosis. Owing to its intrinsic properties like heterogeneity, lack of hormonal receptors and aggressive phenotype leave chemotherapy as a mainstay for the treatment of TNBC. Various studies have demonstrated that chemotherapy alone or therapeutic drugs targeting TNBC pathways, epigenetic mechanisms and immunotherapy alone have not shown significant improvement in TNBC patients. On the other hand, a combination of therapeutic drugs or addition of chemotherapy with therapeutic drugs has shown substantial improvement in results and proven to be an effective strategy for TNBC treatment. This review sheds light on effective combinational drug strategies and current clinical trial status of various combinatorial drugs for the treatment of TNBC.
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Affiliation(s)
| | - Suresh B Pakala
- Biology Division, Indian Institute of Science Education and Research (IISER) Tirupati, Andhra Pradesh, India
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33
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Bal E, Park HS, Belaid-Choucair Z, Kayserili H, Naville M, Madrange M, Chiticariu E, Hadj-Rabia S, Cagnard N, Kuonen F, Bachmann D, Huber M, Le Gall C, Côté F, Hanein S, Rosti RÖ, Aslanger AD, Waisfisz Q, Bodemer C, Hermine O, Morice-Picard F, Labeille B, Caux F, Mazereeuw-Hautier J, Philip N, Levy N, Taieb A, Avril MF, Headon DJ, Gyapay G, Magnaldo T, Fraitag S, Crollius HR, Vabres P, Hohl D, Munnich A, Smahi A. Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas. Nat Med 2017; 23:1226-1233. [PMID: 28869610 DOI: 10.1038/nm.4368] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 06/14/2017] [Indexed: 12/19/2022]
Abstract
Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupré-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.
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Affiliation(s)
- Elodie Bal
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
| | - Hyun-Sook Park
- Department of Dermatology, Lausanne University Hospital, Hôpital de Beaumont, Lausanne, Switzerland
| | - Zakia Belaid-Choucair
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
- Department of Hematology, Hôpital Necker-Enfants Malades, Paris, France
| | - Hülya Kayserili
- Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey
- Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Magali Naville
- Institut de Biologie de l'ENS (IBENS), École Normale Supérieure, Paris, France
- CNRS, UMR 8197, Paris, France
- INSERM U1024, Paris, France
| | - Marine Madrange
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
| | - Elena Chiticariu
- Department of Dermatology, Lausanne University Hospital, Hôpital de Beaumont, Lausanne, Switzerland
| | - Smail Hadj-Rabia
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
- Department of Dermatology, Hôpital Necker-Enfants Malades, Paris, France
| | - Nicolas Cagnard
- Plateforme Bio-informatique, Structure Fédérative de Recherche Necker, INSERM US24/CNRS, UMS 3633, Paris, France
| | - Francois Kuonen
- Department of Dermatology, Lausanne University Hospital, Hôpital de Beaumont, Lausanne, Switzerland
| | - Daniel Bachmann
- Department of Dermatology, Lausanne University Hospital, Hôpital de Beaumont, Lausanne, Switzerland
| | - Marcel Huber
- Department of Dermatology, Lausanne University Hospital, Hôpital de Beaumont, Lausanne, Switzerland
| | - Cindy Le Gall
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
| | - Francine Côté
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
- Department of Hematology, Hôpital Necker-Enfants Malades, Paris, France
| | - Sylvain Hanein
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
| | - Rasim Özgür Rosti
- Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
- Laboratory of Genome Maintenance, Rockefeller University, New York, New York, USA
| | - Ayca Dilruba Aslanger
- Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Quinten Waisfisz
- Department of Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
| | - Christine Bodemer
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
- Department of Dermatology, Hôpital Necker-Enfants Malades, Paris, France
| | - Olivier Hermine
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
- Department of Hematology, Hôpital Necker-Enfants Malades, Paris, France
- GR-Ex Laboratory of Excellence, IMAGINE Institute, Paris, France
- Centre Référence Nationale pour les Mastocytoses, Hôpital Necker-Enfants Malades, Paris, France
| | - Fanny Morice-Picard
- Centre de référence pour les maladies rares de la peau, Service de Dermatologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Bruno Labeille
- Department of Dermatology, Centre Hospitalier Universitaire Nord, Saint-Etienne, France
| | - Frédéric Caux
- Department of Dermatology, Hôpital Avicenne, Bobigny, France
| | - Juliette Mazereeuw-Hautier
- Department of Dermatology, Centre de Référence des Maladies Rares de la Peau, Hôpital Larrey, Toulouse, France
| | - Nicole Philip
- Department of Medical Genetics, Hôpital de la Timone, Marseille, France
- AMU-INSERM, UMR_S910, Faculté de Médecine de Marseille, Marseille, France
| | - Nicolas Levy
- Department of Medical Genetics, Hôpital de la Timone, Marseille, France
- AMU-INSERM, UMR_S910, Faculté de Médecine de Marseille, Marseille, France
| | - Alain Taieb
- Centre de référence pour les maladies rares de la peau, Service de Dermatologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
- INSERM U1035, Université de Bordeaux, Bordeaux, France
| | | | - Denis J Headon
- Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK
| | - Gabor Gyapay
- Genoscope (CEA), CNRS UMR 8030, University of Evry, Evry, France
| | - Thierry Magnaldo
- Institute for Research on Cancer and Aging, CNRS UMR 7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France
| | - Sylvie Fraitag
- Department of Pathological Anatomy, Hôpital Necker-Enfants Malades, Paris, France
| | - Hugues Roest Crollius
- Institut de Biologie de l'ENS (IBENS), École Normale Supérieure, Paris, France
- CNRS, UMR 8197, Paris, France
- INSERM U1024, Paris, France
| | - Pierre Vabres
- Department of Dermatology, Centre Hospitalier Universitaire, Hôpital du Bocage, Dijon, France
| | - Daniel Hohl
- Department of Dermatology, Lausanne University Hospital, Hôpital de Beaumont, Lausanne, Switzerland
| | - Arnold Munnich
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
| | - Asma Smahi
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
- IMAGINE Institute, INSERM UMR 1163, Paris, France
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Monkkonen T, Lewis MT. New paradigms for the Hedgehog signaling network in mammary gland development and breast Cancer. Biochim Biophys Acta Rev Cancer 2017; 1868:315-332. [PMID: 28624497 PMCID: PMC5567999 DOI: 10.1016/j.bbcan.2017.06.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 06/08/2017] [Indexed: 12/12/2022]
Abstract
The Hedgehog signaling network regulates organogenesis, cell fate, proliferation, survival, and stem cell self-renewal in many mammalian tissues. Aberrant activation of the Hedgehog signaling network is present in ~25% of all cancers, including breast. Altered expression of Hedgehog network genes in the mammary gland can elicit phenotypes at many stages of development. However, synthesizing a cohesive mechanistic model of signaling at different stages of development has been difficult. Emerging data suggest that this difficulty is due, in part, to non-canonical and tissue compartment-specific (i.e., epithelial, versus stromal, versus systemic) functions of Hedgehog network components. With respect to systemic functions, Hedgehog network genes regulate development of endocrine organs that impinge on mammary gland development extrinsically. These new observations offer insight into previously conflicting data, and have bearing on the potential for anti-Hedgehog therapeutics in the treatment of breast cancer.
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Affiliation(s)
- Teresa Monkkonen
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; University of California, San Francisco, Dept. of Pathology, 513 Parnassus Ave., San Francisco, CA 94118, USA
| | - Michael T Lewis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Radiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
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MMP11 and CD2 as novel prognostic factors in hormone receptor-negative, HER2-positive breast cancer. Breast Cancer Res Treat 2017; 164:41-56. [PMID: 28409241 PMCID: PMC5487710 DOI: 10.1007/s10549-017-4234-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 04/06/2017] [Indexed: 12/30/2022]
Abstract
Purpose More accurate prediction of patient outcome based on molecular subtype is required to identify patients who will benefit from specific treatments. Methods We selected novel 16 candidate prognostic genes, including 10 proliferation-related genes (p-genes) and 6 immune response-related genes (i-genes), from the gene list identified in our previous study. We then analyzed the association between their expression, measured by quantitative real-time reverse transcription-PCR in formalin-fixed, paraffin-embedded tissues, and clinical outcome in 819 breast cancer patients according to molecular subtype. Results The prognostic significance of clinical and gene variables varied according to the molecular subtype. Univariate analysis showed that positive lymph node status was significantly correlated with the increased risk of distant metastasis in all subtypes except the hormone receptor-negative, HER2-positive (HR−/HER2+) subtype. Most p-genes were significantly associated with poor prognosis in patients with the HR+/HER2− subtype, whereas i-genes correlated with a favorable outcome in patients with HR−/HER2+ breast cancer. In HR−/HER2+ breast cancer, four genes (three i-genes BTN3A2, CD2, and TRBC1 and the p-gene MMP11) were significantly associated with distant metastasis-free survival (DMFS). A new prognostic model for HR−/HER2+ breast cancer based on the expression of MMP11 and CD2 was developed and the DMFS for patients in the high-risk group according to our model was significantly lower than that for those in the low-risk group. Multivariate analyses revealed that our risk score is an independent prognostic factor for DMFS. Moreover, C-index showed that our risk score has a superior prognostic performance to traditional clinicopathological factors. Conclusions Our new prognostic model for HR−/HER2+ breast cancer provides more accurate information on the risk of distant metastasis than traditional clinical prognostic factors and may be used to identify patients with a good prognosis in this aggressive subtype of breast cancer. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4234-4) contains supplementary material, which is available to authorized users.
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Maruthanila VL, Elancheran R, Kunnumakkara AB, Kabilan S, Kotoky J. Recent development of targeted approaches for the treatment of breast cancer. Breast Cancer 2016; 24:191-219. [PMID: 27796923 DOI: 10.1007/s12282-016-0732-1] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 09/18/2016] [Indexed: 12/17/2022]
Abstract
Breast cancer is the most prominent cause of cancer death in women worldwide. The highlights of this review are to provide an overview of the targeted therapeutic agents, challenges with metastatic breast cancer (MBCa), mechanisms of action through Hedgehog/Gli 1 signaling pathway and future prospective. Over a decade of success, several drugs have been approved and are in the advanced stages of clinical trials that target the receptors such as estrogen receptor, growth factor receptor, receptor activator of nuclear factor kappa-B, etc. Currently, several monoclonal antibodies are also used for the treatment of breast cancer. Advances in understanding tumor biology, particularly signaling pathways such as Notch signaling pathway, Hedgehog/Gli 1 signaling pathway, and inhibitors are considered to be important for bone metastasis. These studies may provide vital information for the design and development of new strategies with respect to efficacy, reduction of the side effects, and treatment strategies.
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Affiliation(s)
- V L Maruthanila
- Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, Assam, 781035, India
| | - R Elancheran
- Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, Assam, 781035, India
| | - A B Kunnumakkara
- Department of Biotechnology, Indian Institute of Technology, Guwahati, Assam, 781035, India
| | - S Kabilan
- Department of Chemistry, Annamalai University, Annamalai Nagar, Tamilnadu, 608002, India
| | - Jibon Kotoky
- Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, Assam, 781035, India.
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Habib JG, O'Shaughnessy JA. The hedgehog pathway in triple-negative breast cancer. Cancer Med 2016; 5:2989-3006. [PMID: 27539549 PMCID: PMC5083752 DOI: 10.1002/cam4.833] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 05/26/2016] [Accepted: 06/30/2016] [Indexed: 12/11/2022] Open
Abstract
Treatment of triple‐negative breast cancer (TNBC) remains challenging due to the underlying heterogeneity of this disease coupled with the lack of predictive biomarkers and effective targeted therapies. Intratumoral heterogeneity, particularly enrichment for breast cancer stem cell‐like subpopulations, has emerged as a leading hypothesis for systemic therapy resistance and clinically aggressive course of poor prognosis TNBC. A growing body of literature supports the role of the stem cell renewal Hedgehog (Hh) pathway in breast cancer. Emerging preclinical data also implicate Hh signaling in TNBC pathogenesis. Herein, we review the evidence for a pathophysiologic role of Hh signaling in TNBC and explore mechanisms of crosstalk between the Hh pathway and other key signaling networks as well as their potential implications for Hh‐targeted interventions in TNBC.
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Affiliation(s)
- Joyce G Habib
- Baylor Charles A. Sammons Cancer Center, Dallas, Texas
| | - Joyce A O'Shaughnessy
- Baylor Charles A. Sammons Cancer Center, Dallas, Texas.
- Texas Oncology, Dallas, Texas.
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38
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Bao C, Kim MC, Chen J, Song J, Ko HW, Lee HJ. Sulforaphene Interferes with Human Breast Cancer Cell Migration and Invasion through Inhibition of Hedgehog Signaling. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:5515-5524. [PMID: 27327035 DOI: 10.1021/acs.jafc.6b02195] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Although inhibition of mammary tumorigenesis by isothiocyanates has been widely studied, little is known about the effects of sulforaphene on invasiveness of breast cancer. Here, sulforaphene significantly inhibited the migration and invasion of triple-negative SUM159 human breast cancer cells and suppressed the expression and activity of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). The Hedgehog (Hh) pathway, as an upstream signaling modulator, was significantly suppressed by sulforaphene. In particular, ciliary localization of Gli1 and its nuclear translocation were blocked by sulforaphene in a time-dependent manner. Consistently, downregulation of Hh signaling by vismodegib and Gli1 knockdown reduced the cellular migration and invasion as well as the expression of MMP-2 and MMP-9. These results indicate that the suppression of Hh/Gli1 signaling by sulforaphene may reduce the MMP-2 and MMP-9 activities and cellular invasiveness of human breast cancer cells, suggesting the potential efficacy of sulforaphene against breast cancer invasion and metastasis.
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Affiliation(s)
- Cheng Bao
- Department of Food Science and Technology, Chung-Ang University , Anseong, 456-756, South Korea
| | - Min Chae Kim
- Department of Food Science and Technology, Chung-Ang University , Anseong, 456-756, South Korea
| | - Jing Chen
- Department of Food Science and Technology, Chung-Ang University , Anseong, 456-756, South Korea
| | - Jieun Song
- College of Pharmacy, Dongguk University-Seoul , Goyang, 410-820, South Korea
| | - Hyuk Wan Ko
- College of Pharmacy, Dongguk University-Seoul , Goyang, 410-820, South Korea
| | - Hong Jin Lee
- Department of Food Science and Technology, Chung-Ang University , Anseong, 456-756, South Korea
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MicroRNA-145 functions as a tumor suppressor by targeting matrix metalloproteinase 11 and Rab GTPase family 27a in triple-negative breast cancer. Cancer Gene Ther 2016; 23:258-65. [PMID: 27364572 DOI: 10.1038/cgt.2016.27] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 05/04/2016] [Accepted: 05/04/2016] [Indexed: 12/26/2022]
Abstract
Although increasing evidence has documented that microRNA-145 (miR-145) acts as a tumor suppressor in breast cancer, its exact role in triple-negative breast cancer (TNBC) remains poorly defined. In this study, the expression of miR-145 in human TNBC cells and samples from 30 patients was analyzed by stem-loop real-time PCR. We found that miR-145 was significantly downregulated in TNBC tissues and cells. Upregulating miR-145 in HCC1937 cells dramatically suppressed cell proliferation and induced G1-phase arrest, whereas MDA-MB-231 cells did not show growth inhibition. MiR-145 exhibited an inhibitory role in cell invasion through the post-transcriptional regulation of the novel targets MMP11 and Rab27a in TNBC cells. Additionally, miR-145 silencing could be reversed by 5-aza-2'-deoxycytidine (DAC). These results demonstrated that miR-145 has an inhibitory role in TNBC malignancy by targeting MMP11 and Rab27a, which might be potential therapeutic and diagnostic targets for TNBC.
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40
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Goliwas KF, Miller LM, Marshall LE, Berry JL, Frost AR. Preparation and Analysis of In Vitro Three Dimensional Breast Carcinoma Surrogates. J Vis Exp 2016. [PMID: 27214165 DOI: 10.3791/54004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Three dimensional (3D) culture is a more physiologically relevant method to model cell behavior in vitro than two dimensional culture. Carcinomas, including breast carcinomas, are complex 3D tissues composed of cancer epithelial cells and stromal components, including fibroblasts and extracellular matrix (ECM). Yet most in vitro models of breast carcinoma consist only of cancer epithelial cells, omitting the stroma and, therefore, the 3D architecture of a tumor in vivo. Appropriate 3D modeling of carcinoma is important for accurate understanding of tumor biology, behavior, and response to therapy. However, the duration of culture and volume of 3D models is limited by the availability of oxygen and nutrients within the culture. Herein, we demonstrate a method in which breast carcinoma epithelial cells and stromal fibroblasts are incorporated into ECM to generate a 3D breast cancer surrogate that includes stroma and can be cultured as a solid 3D structure or by using a perfusion bioreactor system to deliver oxygen and nutrients. Following setup and an initial growth period, surrogates can be used for preclinical drug testing. Alternatively, the cellular and matrix components of the surrogate can be modified to address a variety of biological questions. After culture, surrogates are fixed and processed to paraffin, in a manner similar to the handling of clinical breast carcinoma specimens, for evaluation of parameters of interest. The evaluation of one such parameter, the density of cells present, is explained, where ImageJ and CellProfiler image analysis software systems are applied to photomicrographs of histologic sections of surrogates to quantify the number of nucleated cells per area. This can be used as an indicator of the change in cell number over time or the change in cell number resulting from varying growth conditions and treatments.
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Affiliation(s)
- Kayla F Goliwas
- Department of Pathology, University of Alabama at Birmingham
| | - Lindsay M Miller
- Department of Biomedical Engineering, University of Alabama at Birmingham
| | - Lauren E Marshall
- Department of Biomedical Engineering, University of Alabama at Birmingham
| | - Joel L Berry
- Department of Biomedical Engineering, University of Alabama at Birmingham
| | - Andra R Frost
- Department of Pathology, University of Alabama at Birmingham;
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Zhang X, Huang S, Guo J, Zhou L, You L, Zhang T, Zhao Y. Insights into the distinct roles of MMP-11 in tumor biology and future therapeutics (Review). Int J Oncol 2016; 48:1783-93. [PMID: 26892540 DOI: 10.3892/ijo.2016.3400] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 01/21/2016] [Indexed: 11/06/2022] Open
Abstract
The biological processes of cancer cells such as tumorigenesis, proliferation, angiogenesis, apoptosis and invasion are greatly influenced by the surrounding microenvironment. The ability of solid malignant tumors to alter the microenvironment represents an important characteristic through which tumor cells are able to acquire specific functions necessary for their malignant biological behaviors. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases with the capacity of remodeling extracellular matrix (ECM) by degrading almost all ECM proteins, which plays essential roles during the invasion and metastasis process of solid malignant tumors, including allowing tumor cells to modify the ECM components and release cytokines, ultimately facilitating protease-dependent tumor progression. MMP-11, also named stromelysin-3, is a member of the stromelysin subgroup belonging to MMPs superfamily, which has been detected in cancer cells, stromal cells and adjacent microenvironment. Differently, MMP-11 exerts a dual effect on tumors. On the one hand MMP-11 promotes cancer development by inhibiting apoptosis as well as enhancing migration and invasion of cancer cells, on the other hand MMP-11 plays a negative role against cancer development via suppressing metastasis in animal models. Overexpression of MMP-11 was discovered in sera of cancer patients compared with normal control group as well as in multiple tumor tissue specimens, such as gastric cancer, breast cancer, and pancreatic cancer. At present, some evidence supports that MMP-11 may work as a significant tumor biomarker for early detection of cancer, tumor staging, prognostic analysis, monitoring recurrence during follow-up and also a potential target for immunotherapy against cancer. In view of the importance of MMP-11 in modifying tumor microenvironment and potent antitumoral effects on solid tumors, there is an urgent need for a deeper understanding of how MMP-11 modulates tumor progression, and exploring its potential clinical application.
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Affiliation(s)
- Xu Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Shuai Huang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Junchao Guo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Li Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, P.R. China
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Petrovic I, Milivojevic M, Popovic J, Schwirtlich M, Rankovic B, Stevanovic M. SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines. PLoS One 2015; 10:e0143591. [PMID: 26588701 PMCID: PMC4654472 DOI: 10.1371/journal.pone.0143591] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 11/06/2015] [Indexed: 02/08/2023] Open
Abstract
Although there is much evidence showing functional relationship between Hedgehog pathway, in particular Sonic hedgehog, and SOX transcription factors during embryonic development, scarce data are available regarding their crosstalk in cancer cells. SOX18 protein plays an important role in promoting tumor angiogenesis and therefore emerged as a promising potential target in antiangiogenic tumor therapy. Recently it became evident that expression of SOX18 gene in tumors is not restricted to endothelium of accompanying blood and lymphatic vessels, but in tumor cells as well.In this paper we have identified human SOX18 gene as a novel target gene of Hedgehog signaling in cervical carcinoma cell lines. We have presented data showing that expression of SOX18 gene is regulated by GLI1 and GLI2 transcription factors, final effectors of Hedgehog signaling, and that modulation of Hedgehog signaling activity in considerably influence SOX18 expression. We consider important that Hedgehog pathway inhibitors reduced SOX18 expression, thus showing, for the first time, possibility for manipulationwith SOX18 gene expression. In addition, we analyzed the role of SOX18 in malignant potential of cervical carcinoma cell line, and showed that its overexpression has no influence on cells proliferation and viability, but substantially promotes migration and invasion of cells in vitro. Pro-migratory effect of SOX18 suggests its role in promoting malignant spreading, possibly in response to Hedgehog activation.
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Affiliation(s)
- Isidora Petrovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, P.O.BOX 23, 11000 Belgrade, Serbia
- * E-mail:
| | - Milena Milivojevic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, P.O.BOX 23, 11000 Belgrade, Serbia
| | - Jelena Popovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, P.O.BOX 23, 11000 Belgrade, Serbia
| | - Marija Schwirtlich
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, P.O.BOX 23, 11000 Belgrade, Serbia
| | - Branislava Rankovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, P.O.BOX 23, 11000 Belgrade, Serbia
| | - Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, P.O.BOX 23, 11000 Belgrade, Serbia
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Milioli HH, Vimieiro R, Riveros C, Tishchenko I, Berretta R, Moscato P. The Discovery of Novel Biomarkers Improves Breast Cancer Intrinsic Subtype Prediction and Reconciles the Labels in the METABRIC Data Set. PLoS One 2015; 10:e0129711. [PMID: 26132585 PMCID: PMC4488510 DOI: 10.1371/journal.pone.0129711] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 05/12/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The prediction of breast cancer intrinsic subtypes has been introduced as a valuable strategy to determine patient diagnosis and prognosis, and therapy response. The PAM50 method, based on the expression levels of 50 genes, uses a single sample predictor model to assign subtype labels to samples. Intrinsic errors reported within this assay demonstrate the challenge of identifying and understanding the breast cancer groups. In this study, we aim to: a) identify novel biomarkers for subtype individuation by exploring the competence of a newly proposed method named CM1 score, and b) apply an ensemble learning, as opposed to the use of a single classifier, for sample subtype assignment. The overarching objective is to improve class prediction. METHODS AND FINDINGS The microarray transcriptome data sets used in this study are: the METABRIC breast cancer data recorded for over 2000 patients, and the public integrated source from ROCK database with 1570 samples. We first computed the CM1 score to identify the probes with highly discriminative patterns of expression across samples of each intrinsic subtype. We further assessed the ability of 42 selected probes on assigning correct subtype labels using 24 different classifiers from the Weka software suite. For comparison, the same method was applied on the list of 50 genes from the PAM50 method. CONCLUSIONS The CM1 score portrayed 30 novel biomarkers for predicting breast cancer subtypes, with the confirmation of the role of 12 well-established genes. Intrinsic subtypes assigned using the CM1 list and the ensemble of classifiers are more consistent and homogeneous than the original PAM50 labels. The new subtypes show accurate distributions of current clinical markers ER, PR and HER2, and survival curves in the METABRIC and ROCK data sets. Remarkably, the paradoxical attribution of the original labels reinforces the limitations of employing a single sample classifiers to predict breast cancer intrinsic subtypes.
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Affiliation(s)
- Heloisa Helena Milioli
- Priority Research Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Environmental and Life Science, The University of Newcastle, Callaghan, NSW, Australia
| | - Renato Vimieiro
- Priority Research Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- Centro de Informática, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | - Carlos Riveros
- Priority Research Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Electrical Engineering and Computer Science, The University of Newcastle, Callaghan, NSW, Australia
| | - Inna Tishchenko
- Priority Research Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Electrical Engineering and Computer Science, The University of Newcastle, Callaghan, NSW, Australia
| | - Regina Berretta
- Priority Research Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Electrical Engineering and Computer Science, The University of Newcastle, Callaghan, NSW, Australia
| | - Pablo Moscato
- Priority Research Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Electrical Engineering and Computer Science, The University of Newcastle, Callaghan, NSW, Australia
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Spann AL, Yuan K, Goliwas KF, Steg AD, Kaushik DD, Kwon YJ, Frost AR. The presence of primary cilia in cancer cells does not predict responsiveness to modulation of smoothened activity. Int J Oncol 2015; 47:269-79. [PMID: 25997440 DOI: 10.3892/ijo.2015.3006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 04/14/2015] [Indexed: 11/06/2022] Open
Abstract
Primary cilia are microtubule-based organelles that regulate smoothened-dependent activation of the GLI transcription factors in canonical hedgehog signaling. In many cancers, primary cilia are markedly decreased or absent. The lack of primary cilia may inhibit or alter canonical hedgehog signaling and, thereby, interfere in the cellular responsiveness to modulators of smoothened activity. Clinical trials of smoothened antagonists for cancer treatment have shown the best response in basal cell carcinomas, with limited response in other solid tumors. To determine whether the presence or absence of primary cilia in cancer cells will predict their responsiveness to modulation of smoothened activity, we compared the ability of an agonist and/or inhibitor of smoothened (SAG and SANT1, respectively) to modulate GLI-mediated transcription, as measured by GLI1 mRNA level or GLI-luciferase reporter activity, in non-cancer cells with primary cilia (ovarian surface epithelial cells and breast fibroblasts), in cancer cells that cannot assemble primary cilia (MCF7, MDA-MB-231 cell lines), and in cancer cells with primary cilia (SKOV3, PANC1 cell lines). As expected, SAG and SANT1 resulted in appropriate modulation of GLI transcriptional activity in ciliated non-cancer cells, and failed to modulate GLI transcriptional activity in cancer cells without primary cilia. However, there was also no modulation of GLI transcriptional activity in either ciliated cancer cell line. SAG treatment of SKOV3 induced localization of smoothened to primary cilia, as assessed by immunofluorescence, even though there was no increase in GLI transcriptional activity, suggesting a defect in activation of SMO in the primary cilia or in steps later in the hedgehog pathway. In contrast to SKOV3, SAG treatment of PANC1 did not cause the localization of smoothened to primary cilia. Our data demonstrate that the presence of primary cilia in the cancer epithelial cells lines tested does not indicate their responsiveness to smoothened activation or inhibition.
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Affiliation(s)
- Ashley L Spann
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Kun Yuan
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Kayla F Goliwas
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Adam D Steg
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Devanshu D Kaushik
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yeon-Jin Kwon
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Andra R Frost
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Kamdje AHN, Etet PFS, Vecchio L, Tagne RS, Amvene JM, Muller JM, Krampera M, Lukong KE. New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers. World J Clin Cases 2014; 2:769-786. [PMID: 25516852 PMCID: PMC4266825 DOI: 10.12998/wjcc.v2.i12.769] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/12/2014] [Accepted: 09/23/2014] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy, including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin, Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed.
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46
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Colavito SA, Zou MR, Yan Q, Nguyen DX, Stern DF. Significance of glioma-associated oncogene homolog 1 (GLI1) expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway. Breast Cancer Res 2014; 16:444. [PMID: 25252859 PMCID: PMC4303124 DOI: 10.1186/s13058-014-0444-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 09/08/2014] [Indexed: 01/07/2023] Open
Abstract
Introduction The recently identified claudin-low subtype of breast cancer is enriched for cells with stem-like and mesenchymal-like characteristics. This subtype is most often triple-negative (lacking the estrogen and progesterone receptors (ER, PR) as well as lacking epidermal growth factor 2 (HER2) amplification) and has a poor prognosis. There are few targeted treatment options available for patients with this highly aggressive type of cancer. Methods Using a high throughput inhibitor screen, we identified high expression of glioma-associated oncogene homolog 1 (GLI1), the effector molecule of the hedgehog (Hh) pathway, as a critical determinant of cell lines that have undergone an epithelial to mesenchymal transition (EMT). Results High GLI1 expression is a property of claudin-low cells and tumors and correlates with markers of EMT and breast cancer stem cells. Knockdown of GLI1 expression in claudin-low cell lines resulted in reduced cell viability, motility, clonogenicity, self-renewal, and reduced tumor growth of orthotopic xenografts. We observed non-canonical activation of GLI1 in claudin-low and EMT cell lines, and identified crosstalk with the NFκB pathway. Conclusions This work highlights the importance of GLI1 in the maintenance of characteristics of metastatic breast cancer stem cells. Remarkably, treatment with an inhibitor of the NFκB pathway reproducibly reduces GLI1 expression and protein levels. We further provide direct evidence for the binding of the NFκB subunit p65 to the GLI1 promoter in both EMT and claudin-low cell lines. Our results uncover crosstalk between NFκB and GLI1 signals and suggest that targeting these pathways may be effective against the claudin-low breast cancer subtype. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0444-4) contains supplementary material, which is available to authorized users.
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Bao C, Namgung H, Lee J, Park HC, Ko J, Moon H, Ko HW, Lee HJ. Daidzein suppresses tumor necrosis factor-α induced migration and invasion by inhibiting hedgehog/Gli1 signaling in human breast cancer cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2014; 62:3759-67. [PMID: 24724627 DOI: 10.1021/jf500231t] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
In breast cancer, the cytokine tumor necrosis factor-α (TNF-α) induces cell invasion, although the molecular basis of it has not been clearly elucidated. In this study, we investigated the role of daidzein in regulating TNF-α induced cell invasion and the underlying molecular mechanisms. Daidzein inhibited TNF-α induced cellular migration and invasion in estrogen receptor (ER) negative MCF10DCIS.com human breast cancer cells. TNF-α activated Hedgehog (Hh) signaling by enhancing Gli1 nuclear translocation and transcriptional activity, which resulted in increased invasiveness; these effects were blocked by daidzein and the Hh signaling inhibitors, cyclopamine and vismodegib. Moreover, these compounds suppressed TNF-α induced matrix metalloproteinase (MMP)-9 mRNA expression and activity. Taken together, mammary tumor cell invasiveness was stimulated by TNF-α induced activation of Hh signaling; these effects were abrogated by daidzein, which suppressed Gli1 activation, thereby inhibiting migration and invasion.
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Affiliation(s)
- Cheng Bao
- Department of Food Science and Technology, Chung-Ang University , 4726 Seodongdaero, Anseong 456-756, South Korea
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Mills LD, Zhang L, Marler R, Svingen P, Fernandez-Barrena MG, Dave M, Bamlet W, McWilliams RR, Petersen GM, Faubion W, Fernandez-Zapico ME. Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression. J Biol Chem 2014; 289:16516-25. [PMID: 24737325 DOI: 10.1074/jbc.m113.539031] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The role of GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC). Interestingly, in this model, GLI1 played a tumor-protective function, where survival of GKO/KPC mice was reduced compared with KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and severe leukopenia. In vivo and in vitro expression studies identified FAS and FAS ligand (FASL) as potential mediators of this phenomenon. The FAS/FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation and reporter assays identified FAS and FASL as direct targets of GLI1, whereas GKO/KPC mice showed lower levels of this ligand compared with KPC animals. Finally, decreased levels of apoptosis were detected in tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help with the design and analysis of trials targeting GLI1-related pathways.
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Affiliation(s)
| | | | - Ronald Marler
- the Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Scottsdale, Arizona 85259
| | | | | | - Maneesh Dave
- Laboratory of Epigenetics and Chromatin Dynamics
| | | | | | - Gloria M Petersen
- Division of Epidemiology, Mayo Clinic, Rochester, Minnesota 55905 and
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WU DEYAO, LI MIN, WANG LINMAO, ZHOU YUNFENG, ZHOU JIAN, PAN HUIXING, QU PING. microRNA-145 inhibits cell proliferation, migration and invasion by targeting matrix metallopeptidase-11 in renal cell carcinoma. Mol Med Rep 2014; 10:393-8. [DOI: 10.3892/mmr.2014.2149] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 03/17/2014] [Indexed: 11/05/2022] Open
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Kou YB, Zhang SY, Zhao BL, Ding R, Liu H, Li S. Knockdown of MMP11 inhibits proliferation and invasion of gastric cancer cells. Int J Immunopathol Pharmacol 2013; 26:361-70. [PMID: 23755751 DOI: 10.1177/039463201302600209] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Matrix metalloproteinase 11 (MMP11 or stromelysin-3) has recently been reported to play a crucial role in the development and progression of multiple malignancies. The aim of this study was to investigate the function of MMP11 expression in human gastric adenocarcinoma (GAC). Using immunohistochemistry assay, we studied the expression level of MMP11 in GAC and adjacent non-cancerous tissues (ANCT). The association between MMP11 expression and tumor size and pathological grade, as well as metastatic potential was analyzed. Through small hairpin RNA (shRNA)-mediated MMP11 knockdown in SGC-7901 GAC cells, we observed the changes of the biological behaviors of GAC cells. Our results indicated that the rate of positive expression of MMP11 was higher in GAC tissues than in ANCT (55.0 vs 30.0 percent, P=0.025). MMP11 expression had no association with the factors of age or gender of the GAC patients, or the size, pathological staging and lymph node metastases of the tumors (each P greater than 0.05). Furthermore, MMP11 knockdown inhibited the proliferative activities and invasive potential of SGC-7901 GAC cells with decreased expression of IGF-1, PCNA and VEGF. Taken together, our findings demonstrated that MMP11 expression was increased in GAC tissues, but did not correlate with the clinicopathologic features. Knockdown of MMP11 expression could inhibit the proliferation and invasion of GAC cells probably through down-regulation of the IGF-1 signaling pathway, suggesting that MMP11 might be a potential therapeutic target for the treatment of gastric cancer.
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Affiliation(s)
- Y-B Kou
- Department of Gastroenterology, Baoshan Branch Hospital, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai, China
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