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Toubia J, Kusay Y, Maqsood M, Warnock N, Lawrence D, Bracken C, Gregory P, Kan W, Selth L, Conn S, Lopez A, Branford S, Scott H, Kok CH, Goodall G, Schreiber A. TRanscriptome ANalysis of StratifiEd CohorTs (TRANSECT) enables automated assessment of global gene regulation linked to disparate expression in user defined genes and gene sets. NAR Genom Bioinform 2025; 7:lqaf041. [PMID: 40225790 PMCID: PMC11992672 DOI: 10.1093/nargab/lqaf041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/09/2025] [Accepted: 03/27/2025] [Indexed: 04/15/2025] Open
Abstract
Publicly accessible expression data produced by large consortium projects like TCGA and GTEx are increasing in number and size at an unprecedented rate. Their utility cannot be underestimated given the diversity of valuable tools widely used to interrogate these data and the many discoveries of biological and clinical significance already garnered from these datasets. However, there remain undiscovered ways to mine these rich resources and a continuing need to provide researchers with easily accessible and user-friendly applications for complex or bespoke analyses. We introduce TRanscriptome ANalysis of StratifiEd CohorTs (TRANSECT), a bioinformatics application automating the stratification and subsequent differential expression analysis of cohort data to provide further insights into gene regulation. TRANSECT works by defining two groups within a cohort based on disparate expression of a gene or a gene set and subsequently compares the groups for differences in global expression. Akin to reverse genetics minus the inherent requirement of in vitro or in vivo perturbations, cell lines or model organisms and all the while working within natural physiological limits of expression, TRANSECT compiles information about global transcriptomic change and functional outcomes. TRANSECT is freely available as a command line application or online at https://transect.au.
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Affiliation(s)
- John Toubia
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Data and Bioinformatics Innovation, Department of Genetics and Molecular Pathology, SA Pathology, Adelaide 5000, Australia
- Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide 5000, Australia
- Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia
| | - Yasir Kusay
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Data and Bioinformatics Innovation, Department of Genetics and Molecular Pathology, SA Pathology, Adelaide 5000, Australia
- Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide 5000, Australia
- Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia
| | - Muneeza Maqsood
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide 5000, Australia
- Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia
| | - Nicholas I Warnock
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Data and Bioinformatics Innovation, Department of Genetics and Molecular Pathology, SA Pathology, Adelaide 5000, Australia
- Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide 5000, Australia
- Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia
| | - David M Lawrence
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Data and Bioinformatics Innovation, Department of Genetics and Molecular Pathology, SA Pathology, Adelaide 5000, Australia
- Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide 5000, Australia
- Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia
| | - Cameron P Bracken
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia
| | - Philip A Gregory
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia
| | - Winnie L Kan
- Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide 5000, Australia
| | - Luke A Selth
- Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide 5042, South Australia
- Flinders University, College of Medicine and Public Health, Freemasons Centre for Male Health and Wellbeing, Adelaide 5042, Australia
| | - Simon J Conn
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide 5042, South Australia
| | - Angel F Lopez
- Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia
- Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide 5000, Australia
| | - Susan Branford
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide 5000, Australia
- Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia
| | - Hamish S Scott
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide 5000, Australia
- Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia
| | - Chung Hoow Kok
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Data and Bioinformatics Innovation, Department of Genetics and Molecular Pathology, SA Pathology, Adelaide 5000, Australia
- Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide 5000, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia
| | - Gregory J Goodall
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia
| | - Andreas W Schreiber
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide 5000, Australia
- ACRF Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide 5000, Australia
- School of Biological Sciences, University of Adelaide, Adelaide 5000, Australia
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Otifi HM. Targeting the Inactive Conformation of the Epidermal Growth Factor Receptor Identifies EG31: A Novel Small Molecule Inhibitor Effective Against Normal and 5-Fluorouracil-Resistant Triple Negative Breast Cancer Cells. Onco Targets Ther 2025; 18:617-629. [PMID: 40356744 PMCID: PMC12067978 DOI: 10.2147/ott.s512184] [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: 12/14/2024] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptors, making it difficult to treat with targeted therapies. The Epidermal Growth Factor Receptor (EGFR) is overexpressed in TNBC and is crucial in promoting tumor growth and survival. Despite chemotherapeutics like 5-fluorouracil (5-FU), resistance remains a clinical challenge, underscoring the need for novel therapeutic strategies. Methods High-throughput virtual screening (HTVS) was employed to identify inhibitors targeting the inactive conformation of EGFR. The top-ranked compounds underwent molecular dynamics (MD) simulations and binding free energy calculations using Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA). MDA-MB-231, Hs578T, and 5-FU resistant- MDA-MB-231/5-FUR cells were utilized to assess the anti-proliferative, EGFR, and apoptosis. Results HTVS identified EG31 showing strong binding affinities towards EGFR. MD simulations confirmed the stable binding of EG31 to EGFR, as indicated by consistent Root Mean Square Deviation and hydrogen bond patterns throughout the simulation. MMPBSA calculations revealed highly favorable binding free energies. EG31 inhibited MDA-MB-231 and Hs578T proliferations with GI50 values of 498.90 nM and 740.73 nM, respectively. The compound decreased EGFR-positive populations and favored early and late-phase apoptosis in these cells. Furthermore, EG31 retained the anti-proliferative efficacy in the MDA-MB-231/5-FUR cells, while 5-FU lost its effectiveness by 6-fold. Conclusion This study identified EG31 targeting the inactive conformation of EGFR, offering a promising therapeutic approach to overcome 5-FU resistance in TNBC. Further research could enhance treatment efficacy and provide a new avenue for managing this challenging cancer subtype.
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Affiliation(s)
- Hassan M Otifi
- Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia
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Kang HJ, Kang YW, Lee HY, Ha S, Kim JO, Kim WY, Baik T. Dual Disruption of DNA Repair by a Novel CHK2 Inhibitor, ART-446, and Olaparib is a Promising Strategy for Triple-Negative Breast Cancer Therapy. Biomol Ther (Seoul) 2025; 33:458-469. [PMID: 40195731 PMCID: PMC12059358 DOI: 10.4062/biomolther.2025.029] [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: 02/26/2025] [Revised: 03/07/2025] [Accepted: 03/12/2025] [Indexed: 04/09/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies and is characterized by high recurrence rates and poor prognosis. Recent advances in targeting DNA damage response (DDR) pathways using poly (ADP‒ribose) polymerase (PARP) inhibitors offer promising therapeutic strategies, especially for TNBC patients with BRCA1/2 mutations. This study reports the development and characterization of ART-446, a novel and selective CHK2 inhibitor. ART-446 showed potent activity against TNBC, regardless of BRCA deficiency, and it also reversed PARP inhibitor resistance. ART-446 potently inhibited CHK2 (IC50: 9.06 nM) with high selectivity over other kinases; it synergized with the PARP inhibitor olaparib, enhancing DNA damage, inducing G2/M cell cycle arrest, and promoting apoptosis in both BRCA-mutant and wild-type TNBC cells. Mechanistic analyses revealed that ART-446 sensitized BRCA mutant and WT cells to PARP inhibitors by impairing DNA repair and increasing the accumulation of DNA damage. Importantly, ART-446 disrupted both homologous recombination and nonhomologous end-joining repair pathways, addressing a key limitation of PARP inhibitor monotherapy-resistance in BRCA-proficient cancers. In vivo, the combination of ART-446 and olaparib significantly reduced tumor growth in TNBC xenograft models without noticeable toxicity. The combined treatment increased DNA damage signaling, as evidenced by elevated γH2AX levels, and enhanced the sensitivity of BRCA2-deficient cells to ART-446. These findings underscore the potential of ART-446 to exploit DNA repair deficiencies and overcome resistance mechanisms associated with PARP inhibitors. By addressing the limitations of current treatments and expanding the utility of PARP inhibitors, ART-446 represents a promising candidate for DDR-targeted therapies, offering a novel approach to improve the outcomes of patients with TNBC.
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Affiliation(s)
| | | | - Ha-Young Lee
- Arum therapeutics, Seoul 07793, Republic of Korea
| | - Sojung Ha
- College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Woo-Young Kim
- College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of Korea
| | - Taegon Baik
- Arum therapeutics, Seoul 07793, Republic of Korea
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Sansone C, Pistelli L, Brunet C. The marine xanthophyll diatoxanthin as ferroptosis inducer in MDAMB231 breast cancer cells. Sci Rep 2025; 15:8146. [PMID: 40059233 PMCID: PMC11891320 DOI: 10.1038/s41598-025-91519-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 02/20/2025] [Indexed: 05/13/2025] Open
Abstract
Marine biotopes are considered as a huge reservoir of biodiversity and chemodiversity, the latter potentially providing new treats for health prevention. Among the emphasized marine biocenosis, microorganisms such as microalgae propose suitable solutions to address eco-sustainability or biorefinery topics. The health interests of the xanthophyll diatoxanthin (Dt), a photoprotective and antioxidant pigment synthetized by diatoms, have been recently documented. This study deeply explores the capacity of Dt to intercept cancer progression and addresses the Dt -induced cell death in breast cancer. It is crucial to know which signalling pathway explaining its function is induced by the molecule in the targeted cells. This study disentangled the intracellular effects of Dt in MDAMB231 breast cancer cells. The results highlighted the inhibition of glutathione synthesis through cysteine transport blockage, that in turn, induced an iron accumulation and increase in lipid peroxidation. Those features represent the principal hallmarks of intracellular ferroptosis pathway. Ferroptosis being considered as one of the cell death most promising in fighting cancer development (e.g. in breast cancer) this study reinforces the scientific/biomedical interests on Dt and the diatoms' resource and paves the way to explore its suitability in vivo.
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Affiliation(s)
- Clementina Sansone
- Stazione Zoologica Anton Dohrn, sede Molosiglio, via F. Acton, 80133, Naples, Italy.
| | - Luigi Pistelli
- Stazione Zoologica Anton Dohrn, sede Molosiglio, via F. Acton, 80133, Naples, Italy
- Clinical and Experimental Unit of Breast Cancer, National Cancer Institute, IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Christophe Brunet
- Stazione Zoologica Anton Dohrn, sede Molosiglio, via F. Acton, 80133, Naples, Italy
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Elavarasu SM, Vasudevan K, Sasikumar K, Doss C GP. The role of ABI2 in modulating nuclear proteins: Therapeutic implications for NUP54 and NUP153 in TNBC. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 143:97-115. [PMID: 39843146 DOI: 10.1016/bs.apcsb.2024.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks hormone receptors, which makes it more likely to metastasize and have a poor prognosis. Despite some effectiveness of chemotherapy, TNBC remains challenging to manage, with high relapse and mortality rates. Recent findings have highlighted the role of the ubiquitin-protease system in TNBC, with ABI2 identified as a significant regulator. Reduced ABI2 expression is associated with aggressive disease and poor outcomes, whereas ABI2 overexpression (OE-ABI2) inhibits TNBC cell proliferation by modulating the PI3K/Akt signaling pathway. Although ABI2 is not a nuclear protein, it influences critical nuclear functions such as DNA repair and gene expression. Nuclear proteins, particularly those in the nuclear pore complex and nuclear matrix, are essential for cellular functions and have been linked to various diseases, including cancer. This study used RNA sequencing (RNA-seq) to examine the gene expression in MDA-MB-231 cell line and ABI2-overexpressing cells. Differentially expressed genes were annotated, and a protein-protein interaction network was constructed. Network and enrichment analysis identified the nucleoporins NUP54 and NUP153 as potential novel targets for TNBC. This study emphasizes the impact of ABI2 on nuclear proteins and suggests that targeting NUP54 and NUP153 could offer new therapeutic options for TNBC.
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Affiliation(s)
- Santhosh Mudipalli Elavarasu
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Karthick Vasudevan
- Manipal Academy of Higher Education (MAHE), Manipal, India; Institute of Bioinformatics, International Technology Park, Bangalore, India
| | - K Sasikumar
- Department of Sensor and Biomedical Technology, School of Electronics Engineering, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - George Priya Doss C
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
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Yapar EA, Ozdemir MN, Cavalu S, Dagıstan ÖA, Ozsoy Y, Kartal M. Phytoactive Molecules and Nanodelivery Approaches for Breast Cancer Treatment: Current and Future Perspectives. Curr Pharm Biotechnol 2025; 26:795-812. [PMID: 38859783 DOI: 10.2174/0113892010299183240529094844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/21/2024] [Accepted: 04/29/2024] [Indexed: 06/12/2024]
Abstract
One of the most common malignancies in women, breast cancer accounts for nearly 25% of all cancer cases. Breast cancer is a diverse cancer form that exhibits variability in both morphology and molecular characteristics and is linked to numerous risk factors. Although various approaches and research are ongoing in the treatment and prevention of breast cancer, medication resistance in the current breast cancer treatment contributes to the disease's relapse and recurrence. Phytoactive molecules are the subject of growing research in both breast cancer prevention and treatment, but currently used conventional medicines and techniques limit their application. In recent years, significant advancements have been made in the field of nanotechnology, which has proven to be essential in the fight against drug resistance. The transport of synthetic and natural anticancer molecules via nanocarriers has recently been added to breast cancer therapy, greatly alleviating the constraints of the current approach. In light of these developments, interest in nano-delivery studies of phytoactive molecules has also increased. In this review, research of phytoactive molecules for breast cancers along with their clinical studies and nanoformulations, was presented from current and future perspectives.
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Affiliation(s)
- Evren Algın Yapar
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Sivas Cumhuriyet University, Sivas, Türkiye
| | - Merve Nur Ozdemir
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Sivas Cumhuriyet University, Sivas, Türkiye
| | - Simona Cavalu
- Department of Preclinical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, Bihor, România
| | - Özlem Akbal Dagıstan
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Türkiye
| | - Yıldız Ozsoy
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Türkiye
| | - Murat Kartal
- Faculty of Pharmacy, Bezmialem Vakıf University, Department of Pharmacognosy, Istanbul, Türkiye
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Rajadurai P, Yap NY, Chiew SF, Md Zin RR, Md Pauzi SH, Jaafar ASB, Yahaya A, Looi LM. Prevalence of Programmed Death-Ligand 1 Positivity Using SP142 in Patients With Advanced Stage Triple-Negative Breast Cancer in Malaysia: A Cross-Sectional Study. J Breast Cancer 2024; 27:362-371. [PMID: 39622509 PMCID: PMC11710907 DOI: 10.4048/jbc.2024.0040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/03/2024] [Accepted: 10/29/2024] [Indexed: 01/11/2025] Open
Abstract
PURPOSE Triple-negative breast cancer (TNBC) is a subtype of breast cancer known for its poor prognosis and the absence of viable targets for standard receptor-based therapies. Several studies have suggested that targeting programmed death-ligand 1 (PD-L1) in tumors that express this biomarker, either on tumor cells and/or in the tumor inflammatory infiltrate, may be beneficial in some patients. This study aimed to assess the overall prevalence of PD-L1 positivity using the SP142 antibody clone in patients with advanced TNBC in Malaysia. METHODS This was a multicenter, cross-sectional prevalence study on PD-L1 positivity among patients with advanced-stage TNBC in Malaysia. Patients were identified using medical records and were enrolled in the study if they met the inclusion criteria. PD-L1 evaluation was performed using archived formalin-fixed paraffin-embedded tissue specimens. Demographic and clinical data were also obtained and summarized using descriptive statistics. The association of these parameters with PD-L1 positivity was assessed using chi-square and logistic regression analysis. RESULTS Three medical centers provided 138 complete cases for analysis. Of these 138 cases, 52 (37.7%; 95% confidence interval, 29.6%-46.3%) showed positive PD-L1 expression, defined as immune cell PD-L1 expression ≥ 1%. In a univariate analysis, stage III of the disease and tumor samples from resected specimens were significantly associated with a positive PD-L1 status. However, further assessment using a multivariate model revealed that only resected tumor samples remained significantly associated with PD-L1 positivity after controlling for disease staging. CONCLUSION The prevalence of PD-L1 positivity among patients with stage III or IV TNBC was 37.7%. A significant association was noted between PD-L1 positivity and the tumor tissue obtained from resected specimens. Although the mechanism and clinical significance of this association remain unclear, this finding indicates a possible disparity in the PD-L1 status of samples obtained using surgical resection or biopsy.
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Affiliation(s)
- Pathmanathan Rajadurai
- Laboratory, Subang Jaya Medical Centre, Subang Jaya, Malaysia
- Jeffrey Cheah School of Medicine & Health Sciences, Monash University, Petaling Jaya, Malaysia
- Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.
| | - Ning Yi Yap
- Laboratory, Subang Jaya Medical Centre, Subang Jaya, Malaysia
| | - Seow Fan Chiew
- Department of Pathology, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Reena Rahayu Md Zin
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Suria Hayati Md Pauzi
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | | | - Azyani Yahaya
- Department of Diagnostic Laboratory Service, Hospital Canselor Tuanku Mukhriz, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Lai Meng Looi
- Department of Pathology, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
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Hong L, Tanaka M, Yasui M, Hara-Chikuma M. HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression. Sci Rep 2024; 14:22541. [PMID: 39341960 PMCID: PMC11438890 DOI: 10.1038/s41598-024-73394-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 09/17/2024] [Indexed: 10/01/2024] Open
Abstract
Tumor-associated macrophages (TAMs) originating from monocytes are crucial for cancer progression; however, the mechanism of TAM differentiation is unclear. We investigated factors involved in the differentiation of monocytes into TAMs within the tumor microenvironment of triple-negative breast cancer (TNBC). We screened 172 compounds and found that a heat shock protein 90 (HSP90) inhibitor blocked TNBC-induced monocyte-to-TAM differentiation in human monocytes THP-1. TNBC-derived conditional medium (CM) activated cell signaling pathways, including MAP kinase, AKT and STAT3, and increased the expression of TAM-related genes and proteins. These inductions were suppressed by HSP90 inhibition or by knockdown of HSP90 in TNBC. Additionally, we confirmed that TNBC secreted HSP90 extracellularly and that HSP90 itself promoted TAM differentiation. In a mouse tumor model, treatment with an HSP90 inhibitor suppressed tumor growth and reduced TAMs in the tumor microenvironment. Our findings demonstrate the role of HSP90 in TAM differentiation, suggesting HSP90 as a potential target for TNBC immunotherapy due to its regulatory role in monocyte-to-TAM differentiation.
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Affiliation(s)
- Lingjia Hong
- Department of Pharmacology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Manami Tanaka
- Department of Pharmacology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masato Yasui
- Department of Pharmacology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Mariko Hara-Chikuma
- Department of Pharmacology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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Kim HG, Kim JH, Kim KH, Yoo BC, Kang SU, Kim YB, Kim S, Paik HJ, Lee JE, Nam SJ, Parameswaran N, Han JW, Manavalan B, Cho JY. METTL18 functions as a Phenotypic Regulator in Src-Dependent Oncogenic Responses of HER2-Negative Breast Cancer. Int J Biol Sci 2024; 20:4731-4749. [PMID: 39309445 PMCID: PMC11414398 DOI: 10.7150/ijbs.96487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 08/26/2024] [Indexed: 09/25/2024] Open
Abstract
Methyltransferase-like (METTL)18 has histidine methyltransferase activity on the RPL3 protein and is involved in ribosome biosynthesis and translation elongations. Several studies have reported that actin polymerization serves as a Src regulator, and HSP90 is involved in forming polymerized actin bundles. To understand the role of METTL18 in breast cancer and to demonstrate the importance of METTL18 in HER-2 negative breast cancer metastasis, we used biochemical, molecular biological, and immunological approaches in vitro (breast tumor cell lines), in vivo (tumor xenograft model), and in samples of human breast tumors. A gene expression comparison of 31 METTL series genes and 22 methyltransferases in breast cancer patients revealed that METTL18 is highly amplified in human HER2-negative breast cancer. In addition, elevated levels of METTL18 expression in patients with HER2-negative breast cancer are associated with poor prognosis. Loss of METTL18 significantly reduced the metastatic responses of breast tumor cells in vitro and in vivo. Mechanistically, METTL18 indirectly regulates the phosphorylation of the proto-oncogene tyrosine-protein kinase Src and its downstream molecules in MDA-MB-231 cells via METTL18-mediated RPL3 methylation, which is also involved in determining HSP90 integrity and protein levels. In confocal microscopy and F/G-actin assays, METTL18 was found to induce actin polymerization via HSP90. Molecular events involving METTL18, RPL3, HSP90, and actin polymerization yielded Src phosphorylated at both tyrosine 419 and tyrosine 530 with kinase activity and oncogenic functions. Therefore, it is suggested that the METTL18-HSP90-Actin-Src regulatory axis plays critical oncogenic roles in the metastatic responses of HER2-negative breast cancer and could be a promising therapeutic target.
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Affiliation(s)
- Han Gyung Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Ji Hye Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Kyung-Hee Kim
- Research Institute, National Cancer Center, Goyang 10408, Republic of Korea
| | - Byong Chul Yoo
- Research Institute, National Cancer Center, Goyang 10408, Republic of Korea
| | - Sung-Ung Kang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Young Bong Kim
- Department of Bio-industrial Technologies, Konkuk University, Seoul 05029, Republic of Korea
| | - Sangmin Kim
- Breast Cancer Center, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Hyun-June Paik
- Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Jeong Eon Lee
- Division of Breast, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Seok Jin Nam
- Division of Breast, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Narayanan Parameswaran
- Department of Physiology and Division of Pathology, Michigan State University, East Lansing, MI 48824, USA
| | - Jeung-Whan Han
- Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Balachandran Manavalan
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea
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Hacking SM, Windsor G, Cooper R, Jiao Z, Lourenco A, Wang Y. A novel approach correlating pathologic complete response with digital pathology and radiomics in triple-negative breast cancer. Breast Cancer 2024; 31:529-535. [PMID: 38351366 DOI: 10.1007/s12282-024-01544-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 01/05/2024] [Indexed: 04/26/2024]
Abstract
This rapid communication highlights the correlations between digital pathology-whole slide imaging (WSI) and radiomics-magnetic resonance imaging (MRI) features in triple-negative breast cancer (TNBC) patients. The research collected 12 patients who had both core needle biopsy and MRI performed to evaluate pathologic complete response (pCR). The results showed that higher collagenous values in pathology data were correlated with more homogeneity, whereas higher tumor expression values in pathology data correlated with less homogeneity in the appearance of tumors on MRI by size zone non-uniformity normalized (SZNN). Higher myxoid values in pathology data are correlated with less similarity of gray-level non-uniformity (GLN) in tumor regions on MRIs, while higher immune values in WSIs correlated with the more joint distribution of smaller-size zones by small area low gray-level emphasis (SALGE) in the tumor regions on MRIs. Pathologic complete response (pCR) was associated with collagen, tumor, and myxoid expression in WSI and GLN and SZNN in radiomic features. The correlations of WSI and radiomic features may further our understanding of the TNBC tumoral microenvironment (TME) and could be used in the future to better tailor the use of neoadjuvant chemotherapy (NAC). This communication will focus on the post-NAC MRI features correlated with pCR and their association with WSI features from core needle biopsies.
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Affiliation(s)
- Sean M Hacking
- Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA.
| | - Gabrielle Windsor
- Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Robert Cooper
- Department of Radiology, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Zhicheng Jiao
- Department of Radiology, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Ana Lourenco
- Department of Radiology, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Yihong Wang
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA
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11
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Giovannelli P, Di Donato M, Licitra F, Sabbatino E, Tutino V, Castoria G, Migliaccio A. Filamin A in triple negative breast cancer. Steroids 2024; 205:109380. [PMID: 38311094 DOI: 10.1016/j.steroids.2024.109380] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/06/2024]
Abstract
Triple-negative breast cancer is a rare but highly heterogeneous breast cancer subtype with a limited choice of specific treatments. Chemotherapy remains the only efficient treatment, but its side effects and the development of resistance consolidate the urgent need to discover new targets. In TNBC, filamin A expression correlates to grade and TNM stage. Accordingly, this protein could constitute a new target for this BC subtype. Even if most of the data indicates its direct involvement in cancer progression, some contrasting results underline the need to deepen the studies. To elucidate a possible function of this protein as a TNBC marker, we summarized the main characteristic of filamin A and its involvement in physiological and pathological processes such as cancer. Lastly, we scrutinized its actions in triple-negative breast cancer and highlighted the need to increase the number of studies useful to better clarify the role of this versatile protein as a marker and target in TNBC, alone or in "collaboration" with other proteins with a relevant role in this BC subgroup.
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Affiliation(s)
- Pia Giovannelli
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy.
| | - Marzia Di Donato
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Fabrizio Licitra
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Emilia Sabbatino
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Viviana Tutino
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Gabriella Castoria
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
| | - Antimo Migliaccio
- Department of Precision Medicine, University of Campania "L.Vanvitelli", Via L. De Crecchio, 7-80138 Naples, Italy
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12
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Ram Kumar RM, Logesh R, Joghee S. Breast cancer derived exosomes: Theragnostic perspectives and implications. Clin Chim Acta 2024; 557:117875. [PMID: 38493944 DOI: 10.1016/j.cca.2024.117875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
Breast cancer (BC) is the most prevalent malignancy affecting women worldwide. Although conventional treatments such as chemotherapy, surgery, hormone therapy, radiation therapy, and biological therapy are commonly used, they often entail significant side effects. Therefore, there is a critical need to investigate more cost-effective and efficient treatment modalities in BC. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, play a crucial role in modulating recipient cell behaviour and driving cancer progression. Among the EVs, exosomes provide valuable insights into cellular dynamics under both healthy and diseased conditions. In cancer, exosomes play a critical role in driving tumor progression and facilitating the development of drug resistance. BC-derived exosomes (BCex) dynamically influence BC progression by regulating cell proliferation, immunosuppression, angiogenesis, metastasis, and the development of treatment resistance. Additionally, BCex serve as promising diagnostic markers in BC which are detectable in bodily fluids such as urine and saliva. Targeted manipulation of BCex holds significant therapeutic potential. This review explores the therapeutic and diagnostic implications of exosomes in BC, underscoring their relevance to the disease. Furthermore, it discusses future directions for exosome-based research in BC, emphasizing the necessity for further exploration in this area.
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Affiliation(s)
- Ram Mohan Ram Kumar
- Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India.
| | - Rajan Logesh
- Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
| | - Suresh Joghee
- Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
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13
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Popa CN, Bîrlă R, Daniela D, Iosif C, Chirita E, Mateș IN. Predictive Factors of Neoadjuvant Chemotherapy Response in Breast Cancer Validated by Three Anatomopathological Scores: Residual Cancer Burden, Chevallier System, and Tumor-Infiltrating Lymphocytes. Cureus 2024; 16:e59391. [PMID: 38817506 PMCID: PMC11139452 DOI: 10.7759/cureus.59391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2024] [Indexed: 06/01/2024] Open
Abstract
INTRODUCTION The aim of this retrospective, observational, descriptive study was to identify predictors of response to neoadjuvant therapy in breast cancer patients and to validate them using three anatomopathological scores, such as residual cancer burden (RCB) score, Chevallier system, and tumor-infiltrating lymphocytes (TIL) score. MATERIALS AND METHODS We conducted a study on 88 female patients aged 37 to 78 years with confirmed breast cancer who were indicated for neoadjuvant chemotherapy. We analyzed different individual variables (such as age, menarche, and menopause), clinical/imaging characteristics of the breast tumor and axillary nodes, immunohistochemical biomarkers (such as ER/PR/HER2 and Ki67), and histopathological features (such as subtype and grading) in relation to three anatomopathological scores calculated based on the surgical resection specimen. RESULTS The percentage of patients who could have benefited from conservative surgery increased from 6% at the time of diagnosis to 20% post-primary systemic therapy (PST). Age under 49 (p = 0.01), premenopausal status (p < 0.01), no special type (NST) (p = 0.04), high Ki67 (p < 0.01), triple-negative breast cancer (TNBC) (p = 0.02) are positive predictive factors of neoadjuvant therapy, while lobular/mixt carcinoma-type (p = 0.04), luminal A (p = 0.01), positive lymph node (p < 0.01), and low differentiation grade (p = 0.01) are negative predictive factors for the response to PST. CONCLUSION There is a strong correlation between the RCB score and the Chevallier system for quantifying the response to PST, with most predictive factors being confirmed through appropriate statistical analysis for both. TIL score values correlated with only some of the predictors, most likely due to the importance of calculating this score on both biopsy specimens at diagnosis and resection specimens after chemotherapy.
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Affiliation(s)
- Cristian N Popa
- Faculty of Medicine, University of Medicine and Pharmacy "Carol Davila", Bucharest, ROU
- Department of General Surgery I, "Sf. Maria" Clinical Hospital, Bucharest, ROU
| | - Rodica Bîrlă
- Faculty of Medicine, University of Medicine and Pharmacy "Carol Davila", Bucharest, ROU
- Department of General Surgery I, "Sf. Maria" Clinical Hospital, Bucharest, ROU
| | - Dinu Daniela
- Faculty of Medicine, University of Medicine and Pharmacy "Carol Davila", Bucharest, ROU
- Department of General Surgery I, "Sf. Maria" Clinical Hospital, Bucharest, ROU
| | - Cristina Iosif
- Department of Pathology, "Sf. Maria" Clinical Hospital, Bucharest, ROU
| | - Evelina Chirita
- Department of Oncology, "Sf. Maria" Clinical Hospital, Bucharest, ROU
| | - Ioan Nicolae Mateș
- Faculty of Medicine, University of Medicine and Pharmacy "Carol Davila", Bucharest, ROU
- Department of General Surgery I, "Sf. Maria" Clinical Hospital, Bucharest, ROU
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14
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James AR, Jayaprakash S, Sundeep LM. In-Vitro Cytotoxicity, Apoptotic Property, and Gene Expression Changes Induced by Naringenin-7-O-Glucoside in Triple-Negative Breast Cancer. Cureus 2024; 16:e58634. [PMID: 38770462 PMCID: PMC11104259 DOI: 10.7759/cureus.58634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2024] [Indexed: 05/22/2024] Open
Abstract
INTRODUCTION Cancer is one of the most significant health challenges demanding the expansion of effectual therapeutic methods. Triple-negative breast cancer (TNBC) is a form of aggressive cancer with inadequate therapeutic options which lacks the expression of certain hormones. MATERIALS AND METHODS The present study investigates the potential of naringenin-7-O-glucoside, a flavanone glycoside extracted from Holarrhena antidysenterica as an anticancer agent against TNBC cell lines. In-vitro analysis to evaluate cytotoxicity, apoptotic-inducing properties and effect on gene expression was conducted. RESULTS MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay studied the IC-50 of naringenin-7-O-glucoside to be 233.56 µg/µL, revealing the dose-dependent cytotoxicity with minimal effect on Vero cells. Extensive DNA fragmentation confirmed the apoptotic property. Furthermore, a significant downregulation of the epidermal growth factor receptor (EGFR) was noted in treated cells when equated to the control specimen of the sample. CONCLUSION Therefore, naringenin-7-O-glucoside can be a potential targeted therapeutic agent.
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Affiliation(s)
- Akhila R James
- Biotechnology, Hindustan Institute of Technology and Science, Chennai, IND
| | | | - Lakshmi M Sundeep
- Biotechnology, Hindustan Institute of Technology and Science, Chennai, IND
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15
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Bidany-Mizrahi T, Shweiki A, Maroun K, Abu-Tair L, Mali B, Aqeilan RI. Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection. Cell Death Discov 2024; 10:145. [PMID: 38499540 PMCID: PMC10948869 DOI: 10.1038/s41420-024-01878-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 02/07/2024] [Accepted: 02/20/2024] [Indexed: 03/20/2024] Open
Abstract
Breast cancer is the leading cause of cancer-related deaths in women worldwide, with the basal-like or triple-negative breast cancer (TNBC) subtype being particularly aggressive and challenging to treat. Understanding the molecular mechanisms driving the development and progression of TNBC is essential. We previously showed that WW domain-containing oxidoreductase (WWOX) is commonly inactivated in TNBC and is implicated in the DNA damage response (DDR) through ATM and ATR activation. In this study, we investigated the interplay between WWOX and BRCA1, both frequently inactivated in TNBC, on mammary tumor development and on DNA double-strand break (DSB) repair choice. We generated and characterized a transgenic mouse model (K14-Cre;Brca1fl/fl;Wwoxfl/fl) and observed that mice lacking both WWOX and BRCA1 developed basal-like mammary tumors and exhibited a decrease in 53BP1 foci and an increase in RAD51 foci, suggesting impaired DSB repair. We examined human TNBC cell lines harboring wild-type and mutant BRCA1 and found that WWOX expression promoted NHEJ repair in cells with wild-type BRCA1. Our findings suggest that WWOX and BRCA1 play an important role in DSB repair pathway choice in mammary epithelial cells, underscoring their functional interaction and significance in breast carcinogenesis.
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Affiliation(s)
- Tirza Bidany-Mizrahi
- The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Aya Shweiki
- The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Kian Maroun
- The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Lina Abu-Tair
- The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Bella Mali
- Department of Pathology, Hadassah University Hospital, Jerusalem, Israel
| | - Rami I Aqeilan
- The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
- Cyprus Cancer Research Institute (CCRI), Nicosia, Cyprus.
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16
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Khan M, Sunkara V, Yadav M, Bokhari SFH, Rehman A, Maheen A, Shehryar A, Chilla SP, Nasir M, Niaz H, Choudhari J, Anika NN, Amir M. Ferroptosis and Triple-Negative Breast Cancer: A Systematic Overview of Prognostic Insights and Therapeutic Potential. Cureus 2024; 16:e51719. [PMID: 38318597 PMCID: PMC10838809 DOI: 10.7759/cureus.51719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2024] [Indexed: 02/07/2024] Open
Abstract
In the realm of oncology, the prognosis and treatment of triple-negative breast cancer (TNBC) have long been challenges for researchers and clinicians. Characterized by its aggressive nature and limited therapeutic options, TNBC demands innovative approaches to understanding its underlying mechanisms and improving patient outcomes. One such avenue of exploration that has emerged in recent years is the study of ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation. Ferroptosis has garnered increasing attention due to its potential relevance in the context of TNBC. This systematic review aims to shed light on the intricate interplay between ferroptosis and the prognosis of TNBC. The article delves into a comprehensive examination of the existing literature to provide a holistic understanding of the subject. By investigating ferroptosis as both an intervention and a prognostic factor in TNBC, this article seeks to unravel its potential as a therapeutic target and prognostic marker. The emerging evidence and heterogeneity of ferroptosis in TNBC underscore the need for a systematic approach to assess its impact on patient outcomes. This review will serve as a valuable resource for researchers, clinicians, and healthcare professionals striving to enhance our knowledge of TNBC and explore novel avenues for prognosis and treatment.
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Affiliation(s)
- Mohsin Khan
- Interventional Radiology, Musgrove Park Hospital, Taunton, GBR
| | | | - Mansi Yadav
- Internal Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| | | | | | - Azka Maheen
- Medicine, Gomal Medical College, Dera Ismail Khan, PAK
| | | | - Srikar P Chilla
- Medicine, Care Hospitals, Hyderabad, IND
- School of Health Sciences, University of East London, London, GBR
| | - Maheen Nasir
- Anesthesiology, National University of Medical Sciences, Lahore, PAK
| | - Humaira Niaz
- Internal Medicine, Peshawar Medical College, Peshawar, PAK
| | - Jinal Choudhari
- Research & Academic Affairs, Larkin Community Hospital, Miami, USA
| | - Nabila N Anika
- Medicine, Holy Family Red Crescent Medical College and Hospital, Dhaka, BGD
| | - Maaz Amir
- Internal Medicine, King Edward Medical University, Lahore, PAK
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17
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Al Husban H, Al Rabadi A, Odeh AH, Abu Rumman K, Alkhawaldeh F, Noures H, Abo Ashoor M, Abu Rumman A, Atmeh M, Bawaneh M. Clinical Characteristics and Management of Triple-Negative Breast Cancer (TNBC) in Jordan: A Retrospective Analysis. Cureus 2024; 16:e53053. [PMID: 38410339 PMCID: PMC10896140 DOI: 10.7759/cureus.53053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2024] [Indexed: 02/28/2024] Open
Abstract
Introduction Triple-negative breast cancer (TNBC) is known for its aggressive nature and poor prognosis. Despite its responsiveness to chemotherapy, TNBC presents challenges in terms of survival, recurrence, and mortality rates, particularly in diverse populations. Limited research in the Middle East hampers comprehensive understanding and tailored management. Methods A retrospective study at the King Hussein Medical Center in Jordan between the period 2009 to 2023 explored TNBC patients (n=110) who underwent adjuvant chemotherapy after local excision or modified radical mastectomy (MRM). Data encompassed demographics, clinical variables, and operative details. Statistical analysis employed Wilcoxon and chi-squared tests, examining mortality risks and associations between variables. Results Among 110 TNBC patients (mean age 52), 84% underwent MRM, 16% wide local excision and axillary clearance (WLE&AC). Lymphovascular invasion (LVI) was observed in 41%, linked to higher lymph node positivity. Neoadjuvant therapy preceded MRM in 25% of cases. While 75% had grade III tumors, the prevalence of invasive ductal carcinoma was 85%. Conclusions This study contributes crucial insights into TNBC characteristics and management in Jordan. Despite limitations such as retrospective design and sample size, the findings underscore the need for tailored interventions in TNBC patients, emphasizing the importance of neoadjuvant therapy and vigilant consideration of LVI status in treatment planning. Future longitudinal research should delve into disease progression and treatment outcomes in diverse populations, facilitating optimized TNBC management strategies.
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Affiliation(s)
- Hussein Al Husban
- Department of General Surgery, Jordanian Royal Medical Services, Amman, JOR
| | - Anas Al Rabadi
- Department of General Surgery, Jordanian Royal Medical Services, Amman, JOR
| | - Ala H Odeh
- Department of General Surgery, Jordanian Royal Medical Services, Amman, JOR
| | - Kahled Abu Rumman
- Department of General Surgery, Jordanian Royal Medical Services, Amman, JOR
| | - Feras Alkhawaldeh
- Department of General Surgery, Jordanian Royal Medical Services, Amman, JOR
| | - Haneen Noures
- Department of Pathology, Jordanian Royal Medical Services, Amman, JOR
| | - Mohammad Abo Ashoor
- Department of Clinical Oncology, Jordanian Royal Medical Services, Amman, JOR
| | - Anas Abu Rumman
- Department of General Surgery, Jordanian Royal Medical Services, Amman, JOR
| | - Mousa Atmeh
- Department of Clinical Oncology, Jordanian Royal Medical Services, Amman, JOR
| | - Mohannad Bawaneh
- Department of General Surgery, Jordanian Royal Medical Services, Amman, JOR
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18
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Celik A, Berg T, Jensen MB, Jakobsen E, Nielsen HM, Kümler I, Glavicic V, Jensen JD, Knoop A. Real-World Survival and Treatment Regimens Across First- to Third-Line Treatment for Advanced Triple-Negative Breast Cancer. Breast Cancer (Auckl) 2023; 17:11782234231203292. [PMID: 37810797 PMCID: PMC10552450 DOI: 10.1177/11782234231203292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 08/31/2023] [Indexed: 10/10/2023] Open
Abstract
Background Metastatic triple-negative breast cancer (mTNBC) is an aggressive subtype of breast cancer with poor survival. Currently, the literature lacks comprehensive real-world evidence on locally recurrent and mTNBC patients. To validate the optimal treatment for patients with mTNBC, real-world evidence in combination with data from clinical trials must be evaluated as complementary. Objectives The objective of the study is to examine outcomes and treatment patterns of patients with advanced triple-negative breast cancer (TNBC) utilizing real-world data of patients from all oncology sites across Denmark. Design This is a retrospective, non-interventional, multi-site, population-based observational study conducted across all oncology departments in Denmark. Methods We included all women diagnosed with metastatic or locally recurrent TNBC from January 1, 2017, to December 31, 2019, using the national Danish Breast Cancer Group database. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in the first to third treatment line. Results The study included 243 women diagnosed with metastatic or recurrent TNBC. The median OS (mOS) was 11.6 months after the first line of treatment, 6.5 months after the second line, and 6.5 months after the third line. De novo mTNBC was associated with shorter OS (mOS: 8.3 vs 14.2 months), and those with a relapse within 18 months of primary diagnosis had shorter OS than those with a relapse after 18 months (mOS: 10.0 vs 18.2). In the first line, taxane was the preferred choice of treatment for patients with de novo mTNBC, whereas capecitabine was preferred for patients with recurrent TNBC. Conclusions This real-world, nationwide study demonstrated poor OS among patients with metastatic or recurrent TNBC, with a mOS of 11.6 months (95% CI, 9.9-17.3). Patients who presented with de novo mTNBC or who had a relapse of their breast cancer within 18 months of primary diagnosis had shorter OS. Registration The study was registered and approved by the Danish Capital Regions research overview (P-2021-605).
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Affiliation(s)
- Alan Celik
- Danish Breast Cancer Group (DBCG), Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Tobias Berg
- Danish Breast Cancer Group (DBCG), Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Maj-Britt Jensen
- Danish Breast Cancer Group (DBCG), Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Erik Jakobsen
- Department of Oncology, Hospital of Southern Jutland Sonderborg Branch, Sonderborg, Denmark
| | | | - Iben Kümler
- Department of Oncology, Herlev Hospital, Herlev, Denmark
| | - Vesna Glavicic
- Department of Oncology, Zealand University Hospital, Naestved, Denmark
| | | | - Ann Knoop
- Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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19
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Kamin H, Nolte L, Bleilevens A, Stickeler E, Heinemann D, Maurer J, Johannsmeier S, Ripken T. Imaging and quantification of the tumor microenvironment of triple negative breast cancer using TPEF and scanning laser optical tomography. BIOMEDICAL OPTICS EXPRESS 2023; 14:4579-4593. [PMID: 37791264 PMCID: PMC10545185 DOI: 10.1364/boe.494181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/20/2023] [Accepted: 07/16/2023] [Indexed: 10/05/2023]
Abstract
Triple-negative breast cancer is an aggressive subtype of breast cancer that has a poor five-year survival rate. The tumor's extracellular matrix is a major compartment of its microenvironment and influences the proliferation, migration and the formation of metastases. The study of such dependencies requires methods to analyze the tumor matrix in its native form. In this work, the limits of SHG-microscopy, namely limited penetration depth, sample size and specificity, are addressed by correlative three-dimensional imaging. We present the combination of scanning laser optical tomography (SLOT) and multiphoton microscopy, to depict the matrix collagen on different scales. Both methods can be used complementarily to generate full-volume views and allow for in-depth analysis. Additionally, we explore the use of SHG as a contrast mechanism for complex samples in SLOT. It was possible to depict the overall collagen structure and specific fibers using marker free imaging on different scales. An appropriate sample preparation enables the fixation of the structures while simultaneously conserving the fluorescence of antibody staining. We find that SHG is a suitable contrast mechanism to depict matrix collagen even in complex samples and using SLOT. The insights presented here shall further facilitate the study of the tumor extracellular matrix by correlative 3d imaging.
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Affiliation(s)
- Hannes Kamin
- Industrial and Biomedical Optics Department, Laser Zentrum Hannover e.V., Hollerithallee 8, 30419 Hannover, Germany
| | - Lena Nolte
- Industrial and Biomedical Optics Department, Laser Zentrum Hannover e.V., Hollerithallee 8, 30419 Hannover, Germany
| | - Andreas Bleilevens
- Clinic for Gynecology and Obstetrics, University Hospital Aachen, Pauwelstr. 30, 52074 Aachen, Germany
| | - Elmar Stickeler
- Clinic for Gynecology and Obstetrics, University Hospital Aachen, Pauwelstr. 30, 52074 Aachen, Germany
| | - Dag Heinemann
- Industrial and Biomedical Optics Department, Laser Zentrum Hannover e.V., Hollerithallee 8, 30419 Hannover, Germany
- Department of Phytophotonics, Institute of Horticultural Production Systems, Leibniz University Hannover, Herrenhäuser Str. 2, 30419 Hannover, Germany
- Hannover Centre for Optical Technologies (HOT), Leibniz University Hannover, Nienburger Str. 17, 30167 Hannover, Germany
| | - Jochen Maurer
- Clinic for Gynecology and Obstetrics, University Hospital Aachen, Pauwelstr. 30, 52074 Aachen, Germany
| | - Sonja Johannsmeier
- Industrial and Biomedical Optics Department, Laser Zentrum Hannover e.V., Hollerithallee 8, 30419 Hannover, Germany
- Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, Stadtfelddamm 34, 30625 Hannover, Germany
| | - Tammo Ripken
- Industrial and Biomedical Optics Department, Laser Zentrum Hannover e.V., Hollerithallee 8, 30419 Hannover, Germany
- Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, Stadtfelddamm 34, 30625 Hannover, Germany
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20
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Tiwari PK, Ko TH, Dubey R, Chouhan M, Tsai LW, Singh HN, Chaubey KK, Dayal D, Chiang CW, Kumar S. CRISPR/Cas9 as a therapeutic tool for triple negative breast cancer: from bench to clinics. Front Mol Biosci 2023; 10:1214489. [PMID: 37469704 PMCID: PMC10352522 DOI: 10.3389/fmolb.2023.1214489] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 06/20/2023] [Indexed: 07/21/2023] Open
Abstract
Clustered regularly interspaced short palindromic repeats (CRISPR) is a third-generation genome editing method that has revolutionized the world with its high throughput results. It has been used in the treatment of various biological diseases and infections. Various bacteria and other prokaryotes such as archaea also have CRISPR/Cas9 systems to guard themselves against bacteriophage. Reportedly, CRISPR/Cas9-based strategy may inhibit the growth and development of triple-negative breast cancer (TNBC) via targeting the potentially altered resistance genes, transcription, and epigenetic regulation. These therapeutic activities could help with the complex issues such as drug resistance which is observed even in TNBC. Currently, various methods have been utilized for the delivery of CRISPR/Cas9 into the targeted cell such as physical (microinjection, electroporation, and hydrodynamic mode), viral (adeno-associated virus and lentivirus), and non-viral (liposomes and lipid nano-particles). Although different models have been developed to investigate the molecular causes of TNBC, but the lack of sensitive and targeted delivery methods for in-vivo genome editing tools limits their clinical application. Therefore, based on the available evidences, this review comprehensively highlighted the advancement, challenges limitations, and prospects of CRISPR/Cas9 for the treatment of TNBC. We also underscored how integrating artificial intelligence and machine learning could improve CRISPR/Cas9 strategies in TNBC therapy.
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Affiliation(s)
- Prashant Kumar Tiwari
- Biological and Bio-Computational Lab, Department of Life Sciences, Sharda School of Basic Science and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Tin-Hsien Ko
- Department of Orthopedics, Taipei Medical University Hospital, Taipei City, Taiwan
| | - Rajni Dubey
- Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei City, Taiwan
| | - Mandeep Chouhan
- Biological and Bio-Computational Lab, Department of Life Sciences, Sharda School of Basic Science and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Lung-Wen Tsai
- Department of Medicine Research, Taipei Medical University Hospital, Taipei City, Taiwan
- Department of Information Technology Office, Taipei Medical University Hospital, Taipei City, Taiwan
- Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei City, Taiwan
| | - Himanshu Narayan Singh
- Department of Systems Biology, Columbia University Irving Medical Centre, New York, NY, United States
| | - Kundan Kumar Chaubey
- Division of Research and Innovation, School of Applied and Life Sciences, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Deen Dayal
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, India
| | - Chih-Wei Chiang
- Department of Orthopedics, Taipei Medical University Hospital, Taipei City, Taiwan
- Department of Orthopedic Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Sanjay Kumar
- Biological and Bio-Computational Lab, Department of Life Sciences, Sharda School of Basic Science and Research, Sharda University, Greater Noida, Uttar Pradesh, India
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21
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Lin CH, Lin WD, Huang YC, Chen YC, Loh ZJ, Ger LP, Lin FC, Li HY, Cheng HC, Lee KH, Hsiao M, Lu PJ. Carboxyl-terminal modulator protein facilitates tumor metastasis in triple-negative breast cancer. Cancer Gene Ther 2023; 30:404-413. [PMID: 36400965 PMCID: PMC10014580 DOI: 10.1038/s41417-022-00559-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/18/2022] [Accepted: 10/28/2022] [Indexed: 11/19/2022]
Abstract
Currently, the survival rate for breast cancer is more than 90%, but once the cancer cells metastasize to distal organs, the survival rate is dramatically reduced, to less than 30%. Triple-negative breast cancer accounts for 15-20% of all breast cancers. Triple-negative breast cancer (TNBC) is associated with poor prognostic and diagnostic outcomes due to the limiting therapeutic strategies, relative to non-TNBC breast cancers. Therefore, the development of targeted therapy for TNBC metastasis remains an urgent issue. In this study, high Carboxyl-terminal modulator protein (CTMP) is significantly associated with recurrence and disease-free survival rate in TNBC patients. Overexpression of CTMP promotes migration and invasion abilities in BT549 cells. Down-regulating of CTMP expression inhibits migration and invasion abilities in MDA-MB-231 cells. In vivo inoculation of high-CTMP cells enhances distant metastasis in mice. The metastasis incidence rate is decreased in mice injected with CTMP-downregulating MDA-MB-231 cells. Gene expression microarray analysis indicates the Akt-dependent pathway is significantly enhanced in CTMP overexpressing cells compared to the parental cells. Blocking Akt activation via Akt inhibitor treatment or co-expression of the dominant-negative form of Akt proteins successfully abolishes the CTMP mediating invasion in TNBC cells. Our findings suggest that CTMP is a potential diagnostic marker for recurrence and poor disease-free survival in TNBC patients. CTMP promotes TNBC metastasis via the Akt-activation-dependent pathway.
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Affiliation(s)
- Cheng-Han Lin
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan
| | - Wen-Der Lin
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan
| | - Yun-Chin Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan
| | - Yu-Chia Chen
- Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, 813414, Taiwan
| | - Zhu-Jun Loh
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan
| | - Luo-Ping Ger
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, 813414, Taiwan
| | - Forn-Chia Lin
- Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan, 70401, Taiwan
| | - Hao-Yi Li
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan
| | - Hui-Chuan Cheng
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan
| | - Kuen-Haur Lee
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
| | - Michael Hsiao
- Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan
| | - Pei-Jung Lu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan.
- Department of Clinical Medicine Research, National Cheng Kung University Hospital, Tainan, 70401, Taiwan.
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22
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Fu Z, Chen S, Zhu Y, Zhang D, Xie P, Jiao Q, Chi J, Xu S, Xue Y, Lu X, Song X, Cristofanilli M, Gradishar WJ, Kalinsky K, Yin Y, Zhang B, Wan Y. Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity. SCIENCE ADVANCES 2023; 9:eadd6626. [PMID: 36608132 PMCID: PMC9821867 DOI: 10.1126/sciadv.add6626] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 12/06/2022] [Indexed: 05/24/2023]
Abstract
Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that elevation of CD73 levels due to its aberrant turnover is correlated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs). We have identified TRIM21 as an E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8+ T cell function. Replacement of lysine 133, 208, 262, and 321 residues by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM21high/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation.
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Affiliation(s)
- Ziyi Fu
- Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Siqi Chen
- Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yueming Zhu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA
| | - Donghong Zhang
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Ping Xie
- Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Qiao Jiao
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Junlong Chi
- Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Shipeng Xu
- Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yifan Xue
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xinghua Lu
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xinxin Song
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - William J. Gradishar
- Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Kevin Kalinsky
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bin Zhang
- Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yong Wan
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
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23
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Katheeja MN, Das SP, Das R, Laha S. BRCA1 interactors, RAD50 and BRIP1, as prognostic markers for triple-negative breast cancer severity. Front Genet 2023; 14:1035052. [PMID: 36873936 PMCID: PMC9978165 DOI: 10.3389/fgene.2023.1035052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 01/30/2023] [Indexed: 02/18/2023] Open
Abstract
Introduction: BRIP1 (BRCA1-interacting protein 1) is one of the major interacting partners of BRCA1, which plays an important role in repair by homologous recombination (HR). This gene is mutated in around 4% of cases of breast cancer; however, its mechanism of action is unclear. In this study, we presented the fundamental role of BRCA1 interactors BRIP1 and RAD50 in the development of differential severity in triple-negative breast cancer (TNBC) among various affected individuals. Methods: We have analyzed the expression of DNA repair-related genes in different BC cells using Real-time PCR and western blotting analysis and assessed changes in stemness property and proliferation through Immunophenotyping. We have performed cell cycle analysis to see the defect in checkpoints and also immunofluorescence assay to confirm the accumulation of gamma-H2AX and BRCA1 foci and subsequent incidence. We have performed a severity analysis using TCGA data sets for comparing the expression in MDA-MB-468 MDA-MB-231 and MCF7 cell line. Results: We showed that in some TNBC cell lines such as MDA-MB-231, the functioning of both BRCA1/TP53 is compromised. Furthermore, the sensing of DNA damage is affected. Due to less damage-sensing capability and low availability of BRCA1 at the damage sites, the repair by HR becomes inefficient, leading to more damage. Accumulation of damage sends a signal for over activation of NHEJ repair pathways. Over expressed NHEJ molecules with compromised HR and checkpoint conditions lead to higher proliferation and error-prone repair, which increases the mutation rate and corresponding tumour severity. The in-silico analysis of the TCGA datasets with gene expression in the deceased population showed a significant correlation of BRCA1 expression with overall survival (OS) in TNBCs (0.0272). The association of BRCA1 with OS became stronger with the addition of BRIP1 expression (0.000876**). Conclusion: The severity phenotypes were more in cells having compromised BRCA1-BRIP1 functioning. Since the OS is directly proportional to the extent of severity, the data analysis hints at the role of BRIP1 in controlling the severity of TNBC.
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Affiliation(s)
- Muhseena N Katheeja
- Yenepoya Research Centre, Yenepoya (Deemed to be) University, Mangalore, Karnataka, India
| | - Shankar Prasad Das
- Yenepoya Research Centre, Yenepoya (Deemed to be) University, Mangalore, Karnataka, India
| | - Ranajit Das
- Yenepoya Research Centre, Yenepoya (Deemed to be) University, Mangalore, Karnataka, India
| | - Suparna Laha
- Yenepoya Research Centre, Yenepoya (Deemed to be) University, Mangalore, Karnataka, India
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24
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Secondary Psychosis Following Neoadjuvant AC-T Chemotherapy for Triple-Negative Breast Cancer: Case Report and Literature Review of Psychosis Postchemotherapy. Case Rep Psychiatry 2022; 2022:4939219. [PMCID: PMC9635971 DOI: 10.1155/2022/4939219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022] Open
Abstract
Triple-negative breast cancer is a unique subtype among breast cancers. Management includes a neoadjuvant chemotherapy regimen. Psychiatric complications of the regimen have not been reported before. We present a case of acute psychosis after the second cycle of chemotherapy in a 42-year-old woman with triple-negative breast cancer. The patient presented with sudden irritability, agitation, disorganization in speech and behavior, and paranoia involving her coworkers conspiring against her and causing her trouble with the law for 4 days. She was in her usual state of health until after her second cycle of chemotherapy. This was the first presentation of psychotic symptoms in her life. She was conscious and oriented. There were no neurologic deficits. She denied any change in her mood and any features of hallucinations. She was uncooperative, restless, had flight of ideas, and persecutory delusions. The remainder of the examination was normal. An autoimmune process, nervous system infection, or psychosis secondary to the chemotherapy were suspected. Serum electrolytes and other biochemical parameters were normal. Imaging of the brain showed no signs of acute brain insults or intracranial metastasis. Cerebrospinal fluid analysis and culture showed no abnormality or growth. The work-up revealed that neurologic, infectious, or autoimmune causes of her psychotic symptoms were less likely. Thus, a diagnosis of psychosis secondary to chemotherapy was considered. Treatment was with paliperidone, risperidone, clonazepam, and sertraline. Over the course of treatment, she showed substantial improvement and completed all of the chemotherapy sessions without adverse effects. In summary, we report a case of a patient whose initial chemotherapy course was complicated by psychosis. Since the neurotoxic and psychiatric effects of chemotherapeutics are not yet sufficiently elucidated, our case emphasizes that early signs of behavioral changes in patients receiving chemotherapy should trigger comprehensive psychiatric evaluation and monitoring of the patient’s mental state.
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25
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Myricetin-induced apoptosis in triple-negative breast cancer cells through inhibition of the PI3K/Akt/mTOR pathway. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:248. [PMID: 36209343 DOI: 10.1007/s12032-022-01856-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/17/2022] [Indexed: 10/10/2022]
Abstract
Breast cancer is still a severe origin of malignant demise in females, and its prevalence is rising worldwide. Triple-negative breast cancer (TNBC) is a diversified aggressive breast tumor distinguished by inadequate prognosis, early recurrence, high invasion, and extremely metastasized disease. Chemotherapy is being used to treat it; however, it has low efficacy. On the other hand, with the growing number of corroborations on subtypes of TNBC and molecular biology of tumors, significant advancement in TNBC targeted treatment has been made. Myricetin (MYR), a polyhydroxyflavonol compound widely found in nature, has been shown to possess anticancer effects in various cancers. Though, the mechanisms and impacts of MYR on metastasis of TNBC remain unclear. Early and late apoptotic cell death and cell proliferation inhibition were observed in MYR-treated TNBC cells. MYR modulated cell cycle, pro-angiogenic, and invasion effects via the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Protein kinase B (PKB/also known as AKT) signaling pathways. Moreover, it regulates the expression of MAPK, PI3K/AKT/mTOR, IκB/NF-κB, Hippo, STAT3, GSK-3β, Nrf2/HO-1, TLR, eNOS / NO, ACE, and AChE. Here, we review the anticancer effects of MYR for TNBC and target the PI3K/AKT/mTOR pathway as a therapeutic target for the fruitful treatment of TNBC to summarize MYR's therapeutic potential.
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26
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Saravanan R, Balasubramanian V, Swaroop Balamurugan SS, Ezhil I, Afnaan Z, John J, Sundaram S, Gouthaman S, Pakala SB, Rayala SK, Venkatraman G. Zinc transporter LIV1: A promising cell surface target for triple negative breast cancer. J Cell Physiol 2022; 237:4132-4156. [PMID: 36181695 DOI: 10.1002/jcp.30880] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/22/2022] [Accepted: 08/30/2022] [Indexed: 11/05/2022]
Abstract
Breast cancer is one of the leading causes contributing to the global cancer burden. The triple negative breast cancer (TNBC) molecular subtype accounts for the most aggressive type. Despite progression in therapeutic options and prognosis in breast cancer treatment options, there remains a high rate of distant relapse. With advancements in understanding the role of zinc and zinc carriers in the prognosis and treatment of the disease, the scope of precision treatment/targeted therapy has been expanded. Zinc levels and zinc transporters play a vital role in maintaining cellular homeostasis, tumor surveillance, apoptosis, and immune function. This review focuses on the zinc transporter, LIV1, as an essential target for breast cancer prognosis and emerging treatment options. Previous studies give an insight into the role of LIV1 in fulfilling the most important hallmarks of cancer such as apoptosis, metastasis, invasion, and evading the immune system. Normal tissue expression of LIV1 is limited. Higher expression of LIV1 has been linked to Epithelial-Mesenchymal Transition, histological grade of cancer, and early node metastasis. LIV1 was found to be one of the attractive targets in the therapeutic hunt for TNBCs. TNBCs are an immunogenic breast cancer subtype. As zinc transporters are known to serve as the metabolic gatekeepers of immune cells, this review bridges tumor infiltrating lymphocytes, TNBC and LIV1. In addition, the suitability of LIV1 as an antibody-drug conjugate (Seattle genetics [SGN]-LIV1A) target in TNBC, represents a promising strategy for patients. Early clinical trial results reveal that this novel agent reduces tumor burden by inducing mitotic arrest, immunomodulation, and immunogenic cell death, warranting further investigation of SGN-LIV1A in combination with immuno-oncology agents. Priming the patient's immune response in combination with SGN-LIV1A could eventually change the landscape for the TNBC patient population.
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Affiliation(s)
- Roshni Saravanan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Vaishnavi Balasubramanian
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Srikanth Swamy Swaroop Balamurugan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Inemai Ezhil
- Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, Tamil Nadu, India
| | - Zeba Afnaan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Jisha John
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Sandhya Sundaram
- Department of Pathology, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Shanmugasundaram Gouthaman
- Department of Surgical Oncology, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Suresh B Pakala
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Suresh Kumar Rayala
- Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, Tamil Nadu, India
| | - Ganesh Venkatraman
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
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27
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Bhise A, Park H, Lee W, Sarkar S, Ha YS, Rajkumar S, Nam B, Lim JE, Huynh PT, Lee K, Son JY, Kim JY, Lee KC, Yoo J. Preclinical Evaluation of hnRNPA2B1 Antibody in Human Triple-Negative Breast Cancer MDA-MB-231 Cells via PET Imaging. Pharmaceutics 2022; 14:pharmaceutics14081677. [PMID: 36015303 PMCID: PMC9415040 DOI: 10.3390/pharmaceutics14081677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/27/2022] [Accepted: 08/09/2022] [Indexed: 11/25/2022] Open
Abstract
Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Because TNBC lacks the expression of commonly targeted receptors, it is challenging to develop a new imaging agent for this cancer subtype. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA–protein complexes that have been linked to tumor development and progression. Considering the high expression of hnRNPA2B1, an hnRNP subtype, in TNBC MDA-MB-231 cells, this study aimed to develop a novel hnRNPA2B1 antibody-based nuclear imaging agent. The hnRNPA2B1-specific antibody was radiolabeled with 64Cu and evaluated in vitro and in vivo. The trans-cyclooctene (TCO) was functionalized on the antibody to obtain hnRNP-PEG4-TCO and reactive tetrazine (Tz) on the ultrastable bifunctional chelator PCB-TE2A-alkyne to yield PCB-TE2A-Tz for the inverse electron demand Diels–Alder reaction. The 64Cu-radiolabeled antibody was administered and imaged at 1–18 h time points for conventional imaging. Alternatively, the unlabeled antibody conjugate was administered, and 48 h later radiolabeled 64Cu-PCB-TE2A-Tz was administered to the same mice for the pretargeting strategy and imaged at the same time intervals for direct comparison. The tumor was successfully visualized in both strategies, and comparatively, pretargeting showed superior results. The 64Cu-PCB-TE2A-Tz was successfully clicked at the tumor site with hnRNP-PEG4-TCO and the non-clicked were concurrently eliminated. This led to increase the tumor uptake with extremely high tumor-to-background ratio manifested by positron emission tomography (PET) imaging and biodistribution studies.
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Affiliation(s)
- Abhinav Bhise
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Hyun Park
- Division of Applied RI, Korea Institute of Radiological and Medical Science, Seoul 01812, Korea
| | - Woonghee Lee
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Swarbhanu Sarkar
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Yeong Su Ha
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Subramani Rajkumar
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Bora Nam
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Jeong Eun Lim
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Phuong Tu Huynh
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Kiwoong Lee
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Ji-Yoon Son
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Jung Young Kim
- Division of Applied RI, Korea Institute of Radiological and Medical Science, Seoul 01812, Korea
| | - Kyo Chul Lee
- Division of Applied RI, Korea Institute of Radiological and Medical Science, Seoul 01812, Korea
| | - Jeongsoo Yoo
- Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea
- Correspondence: ; Tel.: +82-53-420-4947
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28
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Kanabar D, Goyal M, Kane EI, Chavan T, Kabir A, Wang X, Shukla S, Almasri J, Goswami S, Osman G, Kokolis M, Spratt DE, Gupta V, Muth A. Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer. J Med Chem 2022; 65:8975-8997. [PMID: 35758870 PMCID: PMC9524259 DOI: 10.1021/acs.jmedchem.2c00190] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Gankyrin is an oncoprotein responsible for the development of numerous cancer types. It regulates the expression levels of multiple tumor suppressor proteins (TSPs) in liver cancer; however, gankyrin's regulation of these TSPs in breast and lung cancers has not been thoroughly investigated. Additionally, no small-molecule gankyrin inhibitor has been developed which demonstrates potent anti-proliferative activity against gankyrin overexpressing breast and lung cancers. Herein, we are reporting the structure-based design of gankyrin-binding small molecules which potently inhibited the proliferation of gankyrin overexpressing A549 and MDA-MB-231 cancer cells, reduced colony formation, and inhibited the growth of 3D spheroids in an in vitro tumor simulation model. Investigations demonstrated that gankyrin inhibition occurs through either stabilization or destabilization of its 3D structure. These studies shed light on the mechanism of small-molecule inhibition of gankyrin and demonstrate that gankyrin is a viable therapeutic target for the treatment of breast and lung cancer.
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Affiliation(s)
- Dipti Kanabar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
| | - Mimansa Goyal
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
| | - Emma I. Kane
- Gustaf H. Carlson School of Chemistry & Biochemistry, Clark University, Worcester MA 01610, USA
| | - Tejashri Chavan
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
| | - Abbas Kabir
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
| | - Xuechun Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
| | - Snehal Shukla
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
| | - Joseph Almasri
- Department of Chemistry, College of Liberal Arts and Sciences, St. John’s University, Queens NY 11439, USA
| | - Sona Goswami
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
| | - Gizem Osman
- Department of Biological Sciences, College of Liberal Arts and Sciences, St. John’s University, Queens NY 11439, USA
| | - Marino Kokolis
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
| | - Donald E. Spratt
- Gustaf H. Carlson School of Chemistry & Biochemistry, Clark University, Worcester MA 01610, USA
| | - Vivek Gupta
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
| | - Aaron Muth
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences St. John’s University, Queens NY 11439, USA
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Liu H, Muttenthaler M. High Oxytocin Receptor Expression Linked to Increased Cell Migration and Reduced Survival in Patients with Triple-Negative Breast Cancer. Biomedicines 2022; 10:biomedicines10071595. [PMID: 35884900 PMCID: PMC9313263 DOI: 10.3390/biomedicines10071595] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 11/18/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options and high mortality. The oxytocin receptor (OTR) is a class-A G protein-coupled receptor that has been linked to breast cancer, but its role in tumorigenesis and disease progression remains underexplored. OTR expression is highest in tumour-adjacent breast tissue, followed by normal and tumour tissue, indicating a potential role in the tumour microenvironment. OTR levels were higher in migrated MDA-MB-231 cells than in the control parental cells cultured in normal medium; OTR overexpression/knock-down and metastasis biomarker experiments revealed that high OTR expression enhanced metastasis capabilities. These findings align well with data from a murine breast cancer metastasis model, where metastasised tumours had higher OTR expression than the corresponding primary tumours, and high OTR expression also correlates to reduced survival in TNBC patients. OTR agonists/antagonists did not affect MDA-MB-231 cell migration, and pharmacological analysis revealed that the OT/OTR signalling was compromised. High OTR expression enhanced cell migration in an OTR ligand-independent manner, with the underlying mechanism linked to the EGF-mediated ERK1/2-RSK-rpS6 pathway. Taken together, high OTR expression seems to be involved in TNBC metastasis via increasing cell sensitivity to EGF. These results support a potential prognostic biomarker role of OTR and provide new mechanistic insights and opportunities for targeted treatment options for TNBC.
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Affiliation(s)
- Huiping Liu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia;
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, School of Pharmacy, Yantai University, Yantai 264005, China
| | - Markus Muttenthaler
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia;
- Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
- Correspondence: ; Tel.: +61-7-3346-2985; Fax: +61-7-3346-2101
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30
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Kuznetcova I, Bacher F, Alfadul SM, Tham MJR, Ang WH, Babak MV, Rapta P, Arion VB. Elucidation of Structure-Activity Relationships in Indolobenzazepine-Derived Ligands and Their Copper(II) Complexes: the Role of Key Structural Components and Insight into the Mechanism of Action. Inorg Chem 2022; 61:10167-10181. [PMID: 35713376 PMCID: PMC9490829 DOI: 10.1021/acs.inorgchem.2c01375] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Indolo[3,2-d][1]benzazepines (paullones), indolo[3,2-d][2]benzazepines, and indolo[2,3-d][2]benzazepines (latonduines) are isomeric scaffolds of current medicinal interest. Herein, we prepared a small library of novel indolo[3,2-d][2]benzazepine-derived ligands HL1-HL4 and copper(II) complexes 1-4. All compounds were characterized by spectroscopic methods (1H and 13C NMR, UV-vis, IR) and electrospray ionization (ESI) mass spectrometry, while complexes 2 and 3, in addition, by X-ray crystallography. Their purity was confirmed by HPLC coupled with high-resolution ESI mass spectrometry and/or elemental analysis. The stability of compounds in aqueous solutions in the presence of DMSO was confirmed by 1H NMR and UV-vis spectroscopy measurements. The compounds revealed high antiproliferative activity in vitro in the breast cancer cell line MDA-MB-231 and hepatocellular carcinoma cell line LM3 in the low micromolar to nanomolar concentration range. Important structure-activity relationships were deduced from the comparison of anticancer activities of HL1-HL4 and 1-4 with those of structurally similar paullone-derived (HL5-HL7 and 5-7) and latonduine-derived scaffolds (HL8-HL11 and 8-11). The high anticancer activity of the lead drug candidate 4 was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.
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Affiliation(s)
- Irina Kuznetcova
- Institute of Inorganic Chemistry of the University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
| | - Felix Bacher
- Institute of Inorganic Chemistry of the University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
| | - Samah Mutasim Alfadul
- Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, Kowloon, Hong Kong SAR 999077, China
| | - Max Jing Rui Tham
- Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore 117544, Singapore
| | - Wee Han Ang
- Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore 117544, Singapore
| | - Maria V Babak
- Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, Kowloon, Hong Kong SAR 999077, China
| | - Peter Rapta
- Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, SK-81237 Bratislava, Slovak Republic
| | - Vladimir B Arion
- Institute of Inorganic Chemistry of the University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
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31
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The novel STAT3 inhibitor WZ-2-033 causes regression of human triple-negative breast cancer and gastric cancer xenografts. Acta Pharmacol Sin 2022; 43:1013-1023. [PMID: 34267347 PMCID: PMC8976066 DOI: 10.1038/s41401-021-00718-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/14/2021] [Indexed: 02/06/2023]
Abstract
Hyperactive signal transducer and activator of transcription 3 (STAT3) signaling is frequently detected in human triple-negative breast cancer (TNBC) and gastric cancer, leading to uncontrolled tumor growth, resistance to chemotherapy, and poor prognosis. Thus, inhibition of STAT3 signaling is a promising therapeutic approach for both TNBC and gastric cancer, which have high incidences and mortality and limited effective therapeutic approaches. Here, we report a small molecule, WZ-2-033, capable of inhibiting STAT3 activation and dimerization and STAT3-related malignant transformation. We present in vitro evidence from surface plasmon resonance analysis that WZ-2-033 interacts with the STAT3 protein and from confocal imaging that WZ-2-033 disrupts HA-STAT3 and Flag-STAT3 dimerization in intact cells. WZ-2-033 suppresses STAT3-DNA-binding activity but has no effect on STAT5-DNA binding. WZ-2-033 inhibits the phosphorylation and nuclear accumulation of pY705-STAT3 and consequently suppresses STAT3-dependent transcriptional activity and the expression of STAT3 downstream genes. Moreover, WZ-2-033 significantly inhibited the proliferation, colony survival, migration, and invasion of TNBC cells and gastric cancer cells with aberrant STAT3 activation. Furthermore, administration of WZ-2-033 in vivo induced a significant antitumor response in mouse models of TNBC and gastric cancer that correlated with the inhibition of constitutively active STAT3 and the suppression of known STAT3 downstream genes. Thus, our study provides a novel STAT3 inhibitor with significant antitumor activity in human TNBC and gastric cancer harboring persistently active STAT3.
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32
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Wittmann C, Sivchenko AS, Bacher F, Tong KKH, Guru N, Wilson T, Gonzales J, Rauch H, Kossatz S, Reiner T, Babak MV, Arion VB. Inhibition of Microtubule Dynamics in Cancer Cells by Indole-Modified Latonduine Derivatives and Their Metal Complexes. Inorg Chem 2022; 61:1456-1470. [PMID: 34995063 PMCID: PMC8790753 DOI: 10.1021/acs.inorgchem.1c03154] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
![]()
Indolo[2,3-d]benzazepines (indololatonduines)
are rarely discussed in the literature. In this project, we prepared
a series of novel indololatonduine derivatives and their RuII and OsII complexes and investigated their microtubule-targeting
properties in comparison with paclitaxel and colchicine. Compounds
were fully characterized by spectroscopic techniques (1H NMR and UV–vis), ESI mass-spectrometry, and X-ray crystallography,
and their purity was confirmed by elemental analysis. The stabilities
of the compounds in DMSO and water were confirmed by 1H
and 13C NMR and UV–vis spectroscopy. Novel indololatonduines
demonstrated anticancer activity in vitro in a low
micromolar concentration range, while their coordination to metal
centers resulted in a decrease of cytotoxicity. The preliminary in vivo activity of the RuII complex was investigated.
Fluorescence staining and in vitro tubulin polymerization
assays revealed the prepared compounds to have excellent microtubule-destabilizing
activities, even more potent than the well-known microtubule-destabilizing
agent colchicine. Several
synthesized indololatonduine derivatives and their
RuII and OsII complexes were investigated for
their microtubule-targeting properties in comparison with paclitaxel
and colchicine. Fluorescence staining and in vitro tubulin polymerization assays indicate excellent microtubule-destabilizing
activity. The compounds were even more potent than the well-known
microtubule-destabilizing agent colchicine.
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Affiliation(s)
- Christopher Wittmann
- University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090 Vienna, Austria
| | - Anastasiia S Sivchenko
- Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR 999077, PR China
| | - Felix Bacher
- University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090 Vienna, Austria
| | - Kelvin K H Tong
- Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR 999077, PR China
| | - Navjot Guru
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 417 East 68th Street, New York, New York 10065, United States
| | - Thomas Wilson
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 417 East 68th Street, New York, New York 10065, United States
| | - Junior Gonzales
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 417 East 68th Street, New York, New York 10065, United States
| | - Hartmut Rauch
- Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany.,TranslaTUM - Central Institute for Translational Cancer Research, D-81675 Munich, Germany
| | - Susanne Kossatz
- Department of Nuclear Medicine, University Hospital Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany.,TranslaTUM - Central Institute for Translational Cancer Research, D-81675 Munich, Germany.,Department of Chemistry, Technical University of Munich, D-85748 Munich, Germany
| | - Thomas Reiner
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 417 East 68th Street, New York, New York 10065, United States.,Department of Radiology, Weill Cornell Medical College, New York, New York 10021, United States.,Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
| | - Maria V Babak
- Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR 999077, PR China
| | - Vladimir B Arion
- University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090 Vienna, Austria
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Zhang Y, Tong GH, Wei XX, Chen HY, Liang T, Tang HP, Wu CA, Wen GM, Yang WK, Liang L, Shen H. Identification of Five Cytotoxicity-Related Genes Involved in the Progression of Triple-Negative Breast Cancer. Front Genet 2022; 12:723477. [PMID: 35046993 PMCID: PMC8762060 DOI: 10.3389/fgene.2021.723477] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 10/29/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Breast cancer is one of the deadly tumors in women, and its incidence continues to increase. This study aimed to identify novel therapeutic molecules using RNA sequencing (RNA-seq) data of breast cancer from our hospital. Methods: 30 pairs of human breast cancer tissue and matched normal tissue were collected and RNA sequenced in our hospital. Differentially expressed genes (DEGs) were calculated with raw data by the R package "edgeR", and functionally annotated using R package "clusterProfiler". Tumor-infiltrating immune cells (TIICs) were estimated using a website tool TIMER 2.0. Effects of key genes on therapeutic efficacy were analyzed using RNA-seq data and drug sensitivity data from two databases: the Cancer Cell Line Encyclopedia (CCLE) and the Cancer Therapeutics Response Portal (CTRP). Results: There were 2,953 DEGs between cancerous and matched normal tissue, as well as 975 DEGs between primary breast cancer and metastatic breast cancer. These genes were primarily enriched in PI3K-Akt signaling pathway, calcium signaling pathway, cAMP signaling pathway, and cell cycle. Notably, CD8+ T cell, M0 macrophage, M1 macrophage, regulatory T cell and follicular helper T cell were significantly elevated in cancerous tissue as compared with matched normal tissue. Eventually, we found five genes (GALNTL5, MLIP, HMCN2, LRRN4CL, and DUOX2) were markedly corelated with CD8+ T cell infiltration and cytotoxicity, and associated with therapeutic response. Conclusion: We found five key genes associated with tumor progression, CD8+ T cell and therapeutic efficacy. The findings would provide potential molecular targets for the treatment of breast cancer.
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Affiliation(s)
- Yan Zhang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University/Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, The First Affiliated Hospital of Guangdong University Of Pharmacy, Guangzhou, China.,Department of Pathology, Shenzhen Longhua District Maternity & Child Healthcare Hospital, Shenzhen, China
| | - Gui-Hui Tong
- Department of Pathology,The first Affiliated Hospital,Guangzhou Medical University, Guangzhou, China
| | - Xu-Xuan Wei
- Department of Pathology, The First Affiliated Hospital of Guangdong University Of Pharmacy, Guangzhou, China
| | - Hai-Yang Chen
- Department of Pathology, The First Affiliated Hospital of Guangdong University Of Pharmacy, Guangzhou, China
| | - Tian Liang
- Department of Pathology, The First Affiliated Hospital of Guangdong University Of Pharmacy, Guangzhou, China
| | - Hong-Ping Tang
- Department of Pathology, Shenzhen Maternity & Child Healthcare Hospital, Shenzhen, China
| | - Chuan-An Wu
- Department of Prevention and Health Care, Shenzhen Longhua District Maternity & Child Healthcare Hospital, Shenzhen, China
| | - Guo-Ming Wen
- Department of Prevention and Health Care, Shenzhen Longhua District Maternity & Child Healthcare Hospital, Shenzhen, China
| | - Wei-Kang Yang
- Department of Prevention and Health Care, Shenzhen Longhua District Maternity & Child Healthcare Hospital, Shenzhen, China
| | - Li Liang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University/Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Hong Shen
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University/Nanfang Hospital, Southern Medical University, Guangzhou, China
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34
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Berke TP, Slight SH, Hyder SM. Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer. Onco Targets Ther 2022; 15:23-30. [PMID: 35035222 PMCID: PMC8754468 DOI: 10.2147/ott.s342292] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/21/2021] [Indexed: 12/22/2022] Open
Abstract
Tumor suppressor p53 protein (p53) plays a vital role throughout the body to conserve DNA stability and prevent cancer. Normally, wild-type p53 protein (wtp53) is either degraded or bound to a negative regulator and is inactive. When damage to DNA occurs within a cell, p53 protein is induced and causes cell cycle arrest. This gives cells a chance to repair, but if damage is too severe, cells undergo apoptosis and are rejected. Mutations in the p53 gene (mtp53) are associated with a variety of cancers and occur in 70-80% of cases of triple-negative breast cancer (TNBC). Importantly, many mutations occur in the DNA binding domain of p53 gene and the altered mutant p53 protein (mtp53) is subsequently not degraded. High levels of mtp53 protein accumulate within the cell, leading to the development of tumors. Therefore, converting mtp53 protein back into its functional wild-type conformation is a promising means by which to prevent or reverse tumor development. Herein we will briefly examine how tumor suppressor wtp53 exerts its effects, the mechanisms involved in protecting cells that undergo DNA damage and ways in which wtp53 prevents tumorigenesis. Using TNBC as an example, we will describe the use of specific compounds to reactivate mtp53 protein function by reconfiguring its structure and outline the potential benefits of mtp53 protein reactivation. We will also briefly discuss current clinical trials aimed at reactivating mtp53 protein in order to cure certain cancers. Finally, we make the recommendation that greater emphasis should be placed on testing naturally occurring compounds that are generally non-toxic to re-activate mtp53 protein and control progression of TNBC.
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Affiliation(s)
- Taylor P Berke
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65211, USA
| | - Simon H Slight
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65211, USA
- Department of Biomedical Sciences, University of Missouri, Columbia, MO, 65211, USA
| | - Salman M Hyder
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65211, USA
- Department of Biomedical Sciences, University of Missouri, Columbia, MO, 65211, USA
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35
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Subramaniyan V, Fuloria S, Gupta G, Kumar DH, Sekar M, Sathasivam KV, Sudhakar K, Alharbi KS, Al-Malki WH, Afzal O, Kazmi I, Al-Abbasi FA, Altamimi ASA, Fuloria NK. A review on epidermal growth factor receptor's role in breast and non-small cell lung cancer. Chem Biol Interact 2022; 351:109735. [PMID: 34742684 DOI: 10.1016/j.cbi.2021.109735] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/28/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022]
Abstract
Epithelial growth factor receptor (EGFR) is a cell surface transmembrane receptor that mediates the tyrosine signaling pathway to carry the extracellular messages inside the cell and thereby alter the function of nucleus. This leads to the generation of various protein products to up or downregulate the cellular function. It is encoded by cell erythroblastosis virus oncogene B1, so called C-erb B1/ERBB2/HER-2 gene that acts as a proto-oncogene. It belongs to the HER-2 receptor-family in breast cancer and responds best with anti-Herceptin therapy (anti-tyrosine kinase monoclonal antibody). HER-2 positive breast cancer patient exhibits worse prognosis without Herceptin therapy. Similar incidence and prognosis are reported in other epithelial neoplasms like EGFR + lung non-small cell carcinoma and glioblastoma (grade IV brain glial tumor). Present study highlights the role and connectivity of EGF with various cancers via signaling pathways, cell surface receptors mechanism, macromolecules, mitochondrial genes and neoplasm. Present study describes the EGFR associated gene expression profiling (in breast cancer and NSCLC), relation between mitrochondrial genes and carcinoma, and several in vitro and in vivo models to screen the synergistic effect of various combination treatments. According to this study, although clinical studies including targeted treatments, immunotherapies, radiotherapy, TKi-EGFR combined targeted therapy have been carried out to investigate the synergism of combination therapy; however still there is a gap to apply the scenarios of experimental and clinical studies for further developments. This review will give an idea about the transition from experimental to most advanced clinical studies with different combination drug strategies to treat cancer.
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Affiliation(s)
- Vetriselvan Subramaniyan
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jalan SP 2, Bandar Saujana Putra, 42610, Jenjarom, Selangor, Malaysia
| | - Shivkanya Fuloria
- Faculty of Pharmacy & Centre of Excellence for Biomaterials Engineering, AIMST University, Bedong 08100, Kedah, Malaysia
| | - Gaurav Gupta
- Department of Pharmacology, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India; Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical Sciences, Saveetha University, Chennai, India
| | - Darnal Hari Kumar
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selngor, 47500, Malaysia
| | - Mahendran Sekar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, 30450, Malaysia
| | - Kathiresan V Sathasivam
- Faculty of Applied Science & Centre of Excellence for Biomaterials Engineering, AIMST University, Bedong 08100, Kedah, Malaysia
| | - Kalvatala Sudhakar
- School of Pharmaceutical Sciences (LIT-Pharmacy), Lovely Professional University, Jalandhar, 144411, India
| | - Khalid Saad Alharbi
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Waleed Hassan Al-Malki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam BinAbdulaziz University, AlKharj, 11942, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | | | - Neeraj Kumar Fuloria
- Faculty of Pharmacy & Centre of Excellence for Biomaterials Engineering, AIMST University, Bedong 08100, Kedah, Malaysia.
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36
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miR-1205/DNAJB1 reverses docetaxel chemoresistance in human triple negative breast carcinoma cells via regulation of mutp53/TAp63 signaling. Acta Biochim Biophys Sin (Shanghai) 2021; 54:37-46. [PMID: 35130632 PMCID: PMC9909320 DOI: 10.3724/abbs.2021006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Chemoresistance is the major cause of therapeutic failure in human triple negative breast carcinoma (TNBC). Docetaxel (DOC), a first-line therapeutic drug in TNBC treatment, is limited for long-term use due to the development of chemoresistance. Thus, overcoming chemoresistance of DOC remains an important challenge to improve patient's outcome of TNBC. In this study, we aimed to investigate the molecular mechanism behind DOC chemoresistance and the possible therapeutic effects of miRNAs. Utilizing qRT-PCR analysis, we discovered that miR-1205 is gradually downregulated in human triple negative breast carcinoma MDA-MB-231 and docetaxel-resistant MDA-MB-231 (MDA-MB-231/DOC) cells compared with Hs 578Bst normal human breast fibroblasts. Cell viability, cell cycle and apoptosis assays in MDA-MB-231/DOC cells indicated that miR-1205 overexpression enhances docetaxel sensitivity by reducing cell viability as well as inducing G2/M cell cycle arrest and cell apoptosis. Western blot analysis, dual-luciferase reporter assay, co-immunoprecipitation assay and chromatin immunoprecipitation assay revealed that miR-1205 overexpression disrupts the stable complex formation of DNAJB1, mutp53 and TAp63 by directly reducing DNAJB1 expression, which abates the sequestrating effect of mutp53 on TAp63, thereby leading to the enhanced DOC sensitivity in MDA-MB-231/DOC cells. Our findings demonstrate the role of the miR-1205/DNAJB1 axis in the docetaxel resistance of TNBC, which may offer a promising therapeutic approach to resolve docetaxel resistance in TNBC.
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37
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Kumari M, Krishnamurthy PT, Pinduprolu SKSS, Sola P. DR-5 and DLL-4 mAb Functionalized SLNs of Gamma-Secretase Inhibitors- An Approach for TNBC Treatment. Adv Pharm Bull 2021; 11:618-623. [PMID: 34888208 PMCID: PMC8642801 DOI: 10.34172/apb.2021.070] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 08/06/2020] [Accepted: 10/17/2020] [Indexed: 12/16/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive and heterogeneous cancer subtypes. High rates of metastasis, poor prognosis, and drug resistance are the major problems associated with TNBC. The current chemotherapeutics eliminate only the bulk tumor cells (non-BCSCs) and do not affect breast cancer stem cells (BCSCs). The BCSCs which are left behind after chemotherapy is reported to promote recurrence and metastasis of TNBC. Death receptor-5 (DR-5) is exclusively expressed in TNBCs and mediates the extrinsic pathway of apoptosis. DR-5, therefore, can be exploited for targeted drug delivery and to induce apoptosis. Gamma-secretase mediated Notch signaling in BCSCs regulates its proliferation, differentiation, and metastasis. The endogenous ligand, Delta-like ligand 4 (DLL4), is reported to activate this Notch signaling in TNBC. Blocking this signaling pathway using both gamma-secretase inhibitors (GSIs) and DLL4 monoclonal antibody (mAb) may produce synergistic benefits. Further, the GSIs (DAPT, LY-411575, RO4929097, MK0752, etc.) suffer from poor bioavailability and off-target side effects such as diarrhea, suppression of lymphopoiesis, headache, hypertension, fatigue, and ventricular dysfunctions. In this hypothesis, we discuss Solid lipid nanoparticles (SLNs) based drug delivery systems containing GSIs and surface modified with DR-5 and DLL4 monoclonal antibodies (mAb) to effectivity target and treat TNBC. The delivery system is designed to deliver the drug cargo precisely to TNBCs through its DR-5 receptors and hence expected to reduce the off-target side effects of GSIs. Further, DLL4 mAb and GSIs are expected to act synergistically to block the Notch signal mediated BCSCs proliferation, differentiation, and metastasis.
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Affiliation(s)
- Mamta Kumari
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Praveen T Krishnamurthy
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Sai Kiran S S Pinduprolu
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Piyongsola Sola
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
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38
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Guo XM, Yadav MB, Khan M, Hao CW, Lin CY, Huang T, Wu J, Fan BM, Bian ZX. Bradykinin-Potentiating Peptide-Paclitaxel Conjugate Directed at Ectopically Expressed Angiotensin-Converting Enzyme in Triple-Negative Breast Cancer. J Med Chem 2021; 64:17051-17062. [PMID: 34699215 DOI: 10.1021/acs.jmedchem.1c00705] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer with poor prognosis. Here, we present a peptide-drug conjugate (PDC)-bradykinin-potentiating peptide-paclitaxel (BPP-PTX) conjugate-synthesized by conjugating BPP9a with PTX via a succinyl linker. BPP-PTX targets the angiotensin-converting enzyme (ACE) on TNBC cells. ACE was found to be ectopically expressed in two TNBC cell lines but was absent in both the receptor-positive breast cancer cell line and healthy kidney cell line. Overexpression, knockdown, and competitive inhibition experiments demonstrated ACE-mediated cytotoxicity of BPP-PTX. In vivo, ACE-positive tumors were enriched with BPP-PTX, with the PDC being better tolerated than plain PTX. Compared with plain PTX, BPP-PTX exhibited improved tumor-suppressive effects in MDA-MB-468 xenografted female nude mice. Meanwhile, BPP-PTX resulted in less body weight loss and white blood cell reduction toxicity. These results collectively imply the novelty, efficacy, and low-toxicity profile of BPP-PTX as a potential therapeutic for ACE-positive TNBC.
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Affiliation(s)
- Xuan-Ming Guo
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China
| | - Maruti Balaso Yadav
- YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming 650500, P. R. China
| | - Mahjabin Khan
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China
| | - Chao-Wei Hao
- YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming 650500, P. R. China
| | - Cheng-Yuan Lin
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China.,YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming 650500, P. R. China
| | - Tao Huang
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China
| | - Jiang Wu
- Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai Nationalities University, Xining 810007, P. R. China
| | - Bao-Min Fan
- YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming 650500, P. R. China
| | - Zhao-Xiang Bian
- School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon, Hong Kong 999077, P. R. China
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Knab VM, Gotthardt D, Klein K, Grausenburger R, Heller G, Menzl I, Prinz D, Trifinopoulos J, List J, Fux D, Witalisz-Siepracka A, Sexl V. Triple-negative breast cancer cells rely on kinase-independent functions of CDK8 to evade NK-cell-mediated tumor surveillance. Cell Death Dis 2021; 12:991. [PMID: 34689158 PMCID: PMC8542046 DOI: 10.1038/s41419-021-04279-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/24/2021] [Accepted: 10/04/2021] [Indexed: 12/20/2022]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive malignant disease that is responsible for approximately 15% of breast cancers. The standard of care relies on surgery and chemotherapy but the prognosis is poor and there is an urgent need for new therapeutic strategies. Recent in silico studies have revealed an inverse correlation between recurrence-free survival and the level of cyclin-dependent kinase 8 (CDK8) in breast cancer patients. CDK8 is known to have a role in natural killer (NK) cell cytotoxicity, but its function in TNBC progression and immune cell recognition or escape has not been investigated. We have used a murine model of orthotopic breast cancer to study the tumor-intrinsic role of CDK8 in TNBC. Knockdown of CDK8 in TNBC cells impairs tumor regrowth upon surgical removal and prevents metastasis. In the absence of CDK8, the epithelial-to-mesenchymal transition (EMT) is impaired and immune-mediated tumor-cell clearance is facilitated. CDK8 drives EMT in TNBC cells in a kinase-independent manner. In vivo experiments have confirmed that CDK8 is a crucial regulator of NK-cell-mediated immune evasion in TNBC. The studies also show that CDK8 is involved in regulating the checkpoint inhibitor programmed death-ligand 1 (PD-L1). The CDK8-PD-L1 axis is found in mouse and human TNBC cells, underlining the importance of CDK8-driven immune cell evasion in these highly aggressive breast cancer cells. Our data link CDK8 to PD-L1 expression and provide a rationale for investigating the possibility of CDK8-directed therapy for TNBC.
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Affiliation(s)
- Vanessa Maria Knab
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Dagmar Gotthardt
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Klara Klein
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Reinhard Grausenburger
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Gerwin Heller
- Department of Medicine I, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Vienna, Austria
| | - Ingeborg Menzl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Daniela Prinz
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Jana Trifinopoulos
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Julia List
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | - Daniela Fux
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
| | | | - Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
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Yap KM, Sekar M, Seow LJ, Gan SH, Bonam SR, Mat Rani NNI, Lum PT, Subramaniyan V, Wu YS, Fuloria NK, Fuloria S. Mangifera indica (Mango): A Promising Medicinal Plant for Breast Cancer Therapy and Understanding Its Potential Mechanisms of Action. BREAST CANCER (DOVE MEDICAL PRESS) 2021; 13:471-503. [PMID: 34548817 PMCID: PMC8448164 DOI: 10.2147/bctt.s316667] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022]
Abstract
Globally, breast cancer is the most common cancer type and is one of the most significant causes of deaths in women. To date, multiple clinical interventions have been applied, including surgical resection, radiotherapy, endocrine therapy, targeted therapy and chemotherapy. However, 1) the lack of therapeutic options for metastatic breast cancer, 2) resistance to drug therapy and 3) the lack of more selective therapy for triple-negative breast cancer are some of the major challenges in tackling breast cancer. Given the safe nature of natural products, numerous studies have focused on their anti-cancer potentials. Mangifera indica, commonly known as mango, represents one of the most extensively investigated natural sources. In this review, we provide a comprehensive overview of M. indica extracts (bark, kernel, leaves, peel and pulp) and phytochemicals (mangiferin, norathyriol, gallotannins, gallic acid, pyrogallol, methyl gallate and quercetin) reported for in vitro and in vivo anti-breast cancer activities and their underlying mechanisms based on relevant literature from several scientific databases, including PubMed, Scopus and Google Scholar till date. Overall, the in vitro findings suggest that M. indica extracts and/or phytochemicals inhibit breast cancer cell growth, proliferation, migration and invasion as well as trigger apoptosis and cell cycle arrest. In vivo results demonstrated that there was a reduction in breast tumor xenograft growth. Several potential mechanisms underlying the anti-breast cancer activities have been reported, which include modulation of oxidative status, receptors, signalling pathways, miRNA expression, enzymes and cell cycle regulators. To further explore this medicinal plant against breast cancer, future research directions are addressed. The outcomes of the review revealed that M. indica extracts and their phytochemicals may have potential benefits in the management of breast cancer in women. However, to validate its utility in the creation of innovative and potent therapeutic agents to treat breast cancer, more dedicated research, especially clinical studies are needed to explore the anti-breast cancer potentials of M. indica extracts and their phytochemicals.
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Affiliation(s)
- Kah Min Yap
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, 30450, Perak, Malaysia
| | - Mahendran Sekar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, 30450, Perak, Malaysia
| | - Lay Jing Seow
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, 30450, Perak, Malaysia
| | - Siew Hua Gan
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500, Selangor Darul Ehsan, Malaysia
| | - Srinivasa Reddy Bonam
- Institut National de la Santé et de la Recherche Médicale; Centre de Recherche des Cordeliers, Equipe-Immunopathologie et Immunointervention Thérapeutique, Sorbonne Université, Université de Paris, Paris, France
| | - Nur Najihah Izzati Mat Rani
- Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, 30450, Perak, Malaysia
| | - Pei Teng Lum
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, 30450, Perak, Malaysia
| | | | - Yuan Seng Wu
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor, 42610, Malaysia
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Hossain F, Majumder S, David J, Miele L. Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions. Cancers (Basel) 2021; 13:cancers13153739. [PMID: 34359640 PMCID: PMC8345034 DOI: 10.3390/cancers13153739] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/10/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The implementation of precision medicine will revolutionize cancer treatment paradigms. Notably, this goal is not far from reality: genetically similar cancers can be treated similarly. The heterogeneous nature of triple-negative breast cancer (TNBC) made it a suitable candidate to practice precision medicine. Using TNBC molecular subtyping and genomic profiling, a precision medicine-based clinical trial is ongoing. This review summarizes the current landscape and future directions of precision medicine and TNBC. Abstract Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer associated with a high recurrence and metastasis rate that affects African-American women disproportionately. The recent approval of targeted therapies for small subgroups of TNBC patients by the US ‘Food and Drug Administration’ is a promising development. The advancement of next-generation sequencing, particularly somatic exome panels, has raised hopes for more individualized treatment plans. However, the use of precision medicine for TNBC is a work in progress. This review will discuss the potential benefits and challenges of precision medicine for TNBC. A recent clinical trial designed to target TNBC patients based on their subtype-specific classification shows promise. Yet, tumor heterogeneity and sub-clonal evolution in primary and metastatic TNBC remain a challenge for oncologists to design adaptive precision medicine-based treatment plans.
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Affiliation(s)
- Fokhrul Hossain
- Department of Genetics, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA; (S.M.); (L.M.)
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA
- Correspondence:
| | - Samarpan Majumder
- Department of Genetics, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA; (S.M.); (L.M.)
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA
| | - Justin David
- School of Medicine, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA;
| | - Lucio Miele
- Department of Genetics, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA; (S.M.); (L.M.)
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA
- School of Medicine, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA;
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Patwa A, Yamashita R, Long J, Risom T, Angelo M, Keren L, Rubin DL. Multiplexed imaging analysis of the tumor-immune microenvironment reveals predictors of outcome in triple-negative breast cancer. Commun Biol 2021; 4:852. [PMID: 34244605 PMCID: PMC8271023 DOI: 10.1038/s42003-021-02361-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 06/10/2021] [Indexed: 12/18/2022] Open
Abstract
Triple-negative breast cancer, the poorest-prognosis breast cancer subtype, lacks clinically approved biomarkers for patient risk stratification and treatment management. Prior literature has shown that interrogation of the tumor-immune microenvironment may be a promising approach to fill these gaps. Recently developed high-dimensional tissue imaging technology, such as multiplexed ion beam imaging, provide spatial context to protein expression in the microenvironment, allowing in-depth characterization of cellular processes. We demonstrate that profiling the functional proteins involved in cell-to-cell interactions in the microenvironment can predict recurrence and overall survival. We highlight the immunological relevance of the immunoregulatory proteins PD-1, PD-L1, IDO, and Lag3 by tying interactions involving them to recurrence and survival. Multivariate analysis reveals that our methods provide additional prognostic information compared to clinical variables. In this work, we present a computational pipeline for the examination of the tumor-immune microenvironment using multiplexed ion beam imaging that produces interpretable results, and is generalizable to other cancer types.
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Affiliation(s)
- Aalok Patwa
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
- Archbishop Mitty High School, San Jose, CA, USA
| | - Rikiya Yamashita
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
- Center for Artificial Intelligence in Medicine and Imaging, Stanford University, Stanford, CA, USA
| | - Jin Long
- Center for Artificial Intelligence in Medicine and Imaging, Stanford University, Stanford, CA, USA
| | - Tyler Risom
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Michael Angelo
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Leeat Keren
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Daniel L Rubin
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
- Center for Artificial Intelligence in Medicine and Imaging, Stanford University, Stanford, CA, USA.
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Kim J. In silico analysis of differentially expressed genesets in metastatic breast cancer identifies potential prognostic biomarkers. World J Surg Oncol 2021; 19:188. [PMID: 34172056 PMCID: PMC8235641 DOI: 10.1186/s12957-021-02301-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/12/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Identification of specific biological functions, pathways, and appropriate prognostic biomarkers is essential to accurately predict the clinical outcomes of and apply efficient treatment for breast cancer patients. METHODS To search for metastatic breast cancer-specific biological functions, pathways, and novel biomarkers in breast cancer, gene expression datasets of metastatic breast cancer were obtained from Oncomine, an online data mining platform. Over- and under-expressed genesets were collected and the differentially expressed genes were screened from four datasets with large sample sizes (N > 200). They were analyzed for gene ontology (GO), KEGG pathway, protein-protein interaction, and hub gene analyses using online bioinformatic tools (Enrichr, STRING, and Cytoscape) to find enriched functions and pathways in metastatic breast cancer. To identify novel prognostic biomarkers in breast cancer, differentially expressed genes were screened from the entire twelve datasets with any sample sizes and tested for expression correlation and survival analyses using online tools such as KM plotter and bc-GenExMiner. RESULTS Compared to non-metastatic breast cancer, 193 and 144 genes were differentially over- and under-expressed in metastatic breast cancer, respectively, and they were significantly enriched in regulating cell death, epidermal growth factor receptor signaling, and membrane and cytoskeletal structures according to the GO analyses. In addition, genes involved in progesterone- and estrogen-related signalings were enriched according to KEGG pathway analyses. Hub genes were identified via protein-protein interaction network analysis. Moreover, four differentially over-expressed (CCNA2, CENPN, DEPDC1, and TTK) and three differentially under-expressed genes (ABAT, LRIG1, and PGR) were further identified as novel biomarker candidate genes from the entire twelve datasets. Over- and under-expressed biomarker candidate genes were positively and negatively correlated with the aggressive and metastatic nature of breast cancer and were associated with poor and good prognosis of breast cancer patients, respectively. CONCLUSIONS Transcriptome datasets of metastatic breast cancer obtained from Oncomine allow the identification of metastatic breast cancer-specific biological functions, pathways, and novel biomarkers to predict clinical outcomes of breast cancer patients. Further functional studies are needed to warrant validation of their roles as functional tumor-promoting or tumor-suppressing genes.
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Affiliation(s)
- Jongchan Kim
- Department of Life Sciences, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, Republic of Korea.
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Zhao P, Xu Y, Ji W, Zhou S, Li L, Qiu L, Qian Z, Wang X, Zhang H. Biomimetic black phosphorus quantum dots-based photothermal therapy combined with anti-PD-L1 treatment inhibits recurrence and metastasis in triple-negative breast cancer. J Nanobiotechnology 2021; 19:181. [PMID: 34120612 PMCID: PMC8201856 DOI: 10.1186/s12951-021-00932-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/08/2021] [Indexed: 12/23/2022] Open
Abstract
Background Triple-negative breast cancer (TNBC) is a highly aggressive malignant disease with a high rate of recurrence and metastasis, few effective treatment options and poor prognosis. Here, we designed and constructed a combined photothermal immunotherapy strategy based on cancer cell membrane-coated biomimetic black phosphorus quantum dots (BBPQDs) for tumor-targeted photothermal therapy and anti-PD-L1 mediated immunotherapy. Results BBPQDs have good photothermal conversion efficiency and can efficiently target tumor cells through homologous targeting and tumor homing. Under near infrared irradiation, we found that BBPQDs kill tumors directly through photothermal effects and induce dendritic cells maturation. In vivo studies have confirmed that the combined photothermal immunotherapy strategy displays a stronger antitumor activity than anti-PD-L1 monotherapy. In addition, BBPQDs-mediated photothermal therapy in combination with anti-PD-L1 treatment inhibit tumor recurrence and metastasis by reprograming the immunosuppressive tumor microenvironment into an immune-active microenvironment, and promoting the local and systemic antitumor immune response. We further found that the combined photothermal immunotherapy strategy can produce an immune memory effect against tumor rechallenge. Conclusions This study provides a novel therapeutic strategy for inhibiting the recurrence and metastasis of TNBC, with broad application prospects.![]() Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-00932-2.
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Affiliation(s)
- Peiqi Zhao
- Department of Lymphoma, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, 24 Huanhu West Road, Hexi District, Tianjin, 300060, People's Republic of China.
| | - Yuanlin Xu
- Department of Lymphatic Comprehensive Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Wei Ji
- Public Laboratory, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China
| | - Shiyong Zhou
- Department of Lymphoma, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, 24 Huanhu West Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Lanfang Li
- Department of Lymphoma, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, 24 Huanhu West Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Lihua Qiu
- Department of Lymphoma, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, 24 Huanhu West Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Zhengzi Qian
- Department of Lymphoma, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, 24 Huanhu West Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Xianhuo Wang
- Department of Lymphoma, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, 24 Huanhu West Road, Hexi District, Tianjin, 300060, People's Republic of China
| | - Huilai Zhang
- Department of Lymphoma, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, 24 Huanhu West Road, Hexi District, Tianjin, 300060, People's Republic of China.
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Targeted doxorubicin delivery and release within breast cancer environment using PEGylated chitosan nanoparticles labeled with monoclonal antibodies. Int J Biol Macromol 2021; 184:325-338. [PMID: 34119547 DOI: 10.1016/j.ijbiomac.2021.06.014] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 02/07/2023]
Abstract
Breast cancer has been one of the top chronic and life-threatening diseases worldwide. Nano-drug therapeutic systems have proved their efficacy as a selective treatment compared to the traditional ones that are associated with serious adverse effects. Here, biodegradable chitosan nanoparticles (CSNPs) were synthesized to provide selective and sustained release of doxorubicin (DOX) within the breast tumor microenvironment. CSNPs surface was modified using Polyethylene glycol (PEG) to enhance their blood circulation timing. To provide high drug selectivity, CSNPs functionalized with two different types of breast cancer-specific monoclonal antibodies (mAb); anti-human mammaglobin (Anti-hMAM) and anti-human epidermal growth factor (Anti-HER2). Anti-hMAM PEGylated DOX loaded CSNPs and Anti-HER2 PEGylated DOX loaded CSNPs nano-formulations were the most cytotoxic against MCF-7 cancer cells than L-929 normal cells compared to free DOX. Finally, we believe that dose-dependent system toxicity of freely ingested DOX can be managed with such targeted nano-formulated drug delivery platforms.
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Silva Rocha F, da Silva Maués JH, Brito Lins Pereira CM, Moreira-Nunes CA, Rodriguez Burbano RM. Analysis of Increased EGFR and IGF-1R Signaling and Its Correlation with Socio-Epidemiological Features and Biological Profile in Breast Cancer Patients: A Study in Northern Brazil. BREAST CANCER (DOVE MEDICAL PRESS) 2021; 13:325-339. [PMID: 34054308 PMCID: PMC8153070 DOI: 10.2147/bctt.s308554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/02/2021] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Breast cancer (BC) is the second most frequent cancer worldwide. It is known that a subset of BC has amplification, and overexpression of the epidermal growth factor receptor (EGFR) and high expression of the insulin-like growth factor receptor-1 (IGF-1R) are correlated with a favorable prognosis. This study aimed to evaluate the prognostic and predictive values of the EGFR and IGF-1R in tumor samples from patients with BC and their correlation with socio-epidemiological features. PATIENTS AND METHODS We analyzed socio-epidemiological, clinical-pathological data and tumor tissues from 124 patients with BC undergoing treatment, to assess levels of EGFR and IGF-1R mRNA and protein. The predictive performance included the calculation of area-under-the-curve (AUC) to discriminate groups of patients with high and low mRNA expression associated with survival analysis within each molecular group of BC. RESULTS We found a significant expression increase (p <0.001) in EGFR associated with body mass index, angiolymphatic invasion, compromised lymph nodes and follow-up in 58.1% of the triple-negative and HER overexpression tumors. The increase in IGF-IR was significant (p <0.001) in 41.9% of luminal tumors A and B. ROC analysis showed that EGFR had a higher predictive performance (AUC = 0.891) than IGF-1R (AUC = 0.60). The Kaplan-Meier analysis indicated that only the high expression of EGFR was associated with a decreased probability of survival for patients, what did not happen with IGF-1R. CONCLUSION Our results suggest that EGFR and IGF-1R expression patterns associated with the clinical characteristics of patients and biological profile influenced the evolution of BC.
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Affiliation(s)
| | - Jersey Heitor da Silva Maués
- Laboratory of Molecular Biology, Ophir Loyola Hospital, Belém, PA, Brazil
- Laboratory of Human Cytogenetics, Institute of Biological Sciences, Federal University of Pará, Belém, PA, Brazil
| | | | - Caroline Aquino Moreira-Nunes
- Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, Brazil
| | - Rommel Mário Rodriguez Burbano
- Laboratory of Molecular Biology, Ophir Loyola Hospital, Belém, PA, Brazil
- Laboratory of Human Cytogenetics, Institute of Biological Sciences, Federal University of Pará, Belém, PA, Brazil
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Kim H, Son S, Ko Y, Shin I. CTGF regulates cell proliferation, migration, and glucose metabolism through activation of FAK signaling in triple-negative breast cancer. Oncogene 2021; 40:2667-2681. [PMID: 33692467 DOI: 10.1038/s41388-021-01731-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 02/14/2021] [Accepted: 02/22/2021] [Indexed: 01/31/2023]
Abstract
Connective tissue growth factor (CTGF), also known as CCN2, is a member of the CCN protein family of secreted proteins with roles in diverse biological processes. CTGF regulates biological functions such as cell proliferation, migration, adhesion, wound healing, and angiogenesis. In this study, we demonstrate a mechanistic link between CTGF and enhanced aerobic glycolysis in triple-negative breast cancer (TNBC). We found that CTGF is overexpressed in TNBC and high CTGF expression is correlated with a poor prognosis. Also, CTGF was required for in vivo tumorigenesis and in vitro proliferation, migration, invasion, and adhesion of TNBC cells. Our results indicate that extracellular CTGF binds directly to integrin αvβ3, activating the FAK/Src/NF-κB p65 signaling axis, which results in transcriptional upregulation of Glut3. Neutralization of CTGF decreased cell proliferation, migration, and invasion through downregulation of Glut3-mediated glycolytic phenotypes. Overall, our work suggests a novel function for CTGF as a modulator of cancer metabolism, indicating that CTGF is a potential therapeutic target in TNBC.
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Affiliation(s)
- Hyungjoo Kim
- Department of Life Science, Hanyang University, Seoul, 04763, Republic of Korea
| | - Seogho Son
- Department of Life Science, Hanyang University, Seoul, 04763, Republic of Korea
| | - Yunhyo Ko
- Department of Life Science, Hanyang University, Seoul, 04763, Republic of Korea
| | - Incheol Shin
- Department of Life Science, Hanyang University, Seoul, 04763, Republic of Korea. .,Natural Science Institute, Hanyang University, Seoul, 04763, Republic of Korea.
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Sejben A, Vörös A, Golan A, Zombori T, Cserni G. The Added Value of SOX10 Immunohistochemistry to Other Breast Markers in Identifying Cytokeratin 5-Positive Triple Negative Breast Cancers as of Mammary Origin. Pathobiology 2021; 88:228-233. [PMID: 33567441 DOI: 10.1159/000512006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 10/05/2020] [Indexed: 11/19/2022] Open
Abstract
AIMS Triple-negative breast cancer (TNBC) represents a specific group that lacks the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2 and might also lack the expression other breast markers like GATA3, mammaglobin (MG), GCDFP15 (growth cystic disease fluid protein 15), and NYBR1; when this occurs, proving the breast origin of a metastasis is a challenging task. In the present study, we assessed the added value of SOX10 immunohistochemistry to known GATA3, MG, GCDFP15, and NY-BR-1 statuses in a series of CK5-positive primary TNBCs. METHODS Tissue microarrays were made from the formalin-fixed and paraffin-embedded blocks of 120 TNBCs, and 3-4-mm-thick sections were immunostained for SOX10. The cut-off for a positive reaction was at least 10% of tumor cells staining. RESULTS In our cohort, SOX10 positivity was seen in 82/119 cases, 61, 74, 76, and 82 all of which were GATA3, MG, GCDFP15, and NY-BR-1 negative, respectively. Of the SOX10 negative cases, 12 stained with at least another breast marker. Nevertheless, 25/119 (21%) cases remained negative with all markers assessed. DISCUSSION SOX10 proved to be the most commonly positive breast marker in our CK5 expressing TNBCs, but the other markers also had some additive value to SOX10.
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Affiliation(s)
- Anita Sejben
- Department of Pathology, Faculty of Medicine, University of Szeged, Szeged, Hungary,
| | - András Vörös
- Department of Pathology, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Arbel Golan
- Department of Pathology, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Tamás Zombori
- Department of Pathology, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Gábor Cserni
- Department of Pathology, Faculty of Medicine, University of Szeged, Szeged, Hungary.,Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary
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Ashok Kumar P, Paulraj S, Wang D, Huang D, Sivapiragasam A. Associated factors and outcomes of delaying adjuvant chemotherapy in breast cancer by biologic subtypes: a National Cancer Database study. J Cancer Res Clin Oncol 2021; 147:2447-2458. [PMID: 33517468 PMCID: PMC7847714 DOI: 10.1007/s00432-021-03525-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/10/2021] [Indexed: 11/30/2022]
Abstract
Purpose Several studies have evaluated the role of delayed initiation of adjuvant chemotherapy (AC) in breast cancer (BC), but the results have remained controversial and an optimal time has not been defined. Our aim was to determine the effect of time to starting AC from the date of surgery on survival of BC patients, based on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, using data from the National Cancer Database (NCDB). Methods A total of 332,927 Stage I–III BC patients who received AC from 2010 to 2016 were analyzed. We included all ER, PR and HER2 statuses and excluded patients with stage 4 and stage 0 (DCIS) disease. The cohort was divided into five groups based on the time of initiating AC from the date of the most definitive surgery i.e., ≤ 30 days, 31–60 days, 61–90 days, 91–120 days and > 120 days. They were further divided into five subgroups based on the receptor status. Results Hazard ratio (HR) estimates and Kaplan–Meier (KM) analysis shows that starting AC by 31–60 days shows the best survival outcome in all the subtypes, except in hormone positive/HER2 negative BC in which 31–60 days and 61–90 days have similar outcomes. Conclusions After surgery for BC, it takes around 4–6 weeks to begin AC and delay in initiating the same leads to poor outcomes. Our results are particularly significant in triple-negative breast cancer (TNBC), similar to prior studies showing a benefit to starting AC as early as possible after surgery.
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Affiliation(s)
- Prashanth Ashok Kumar
- Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210, USA. .,Department of Internal Medicine, SUNY Upstate Medical University, 750 E Adams Street, Syracuse, NY, 13210, USA.
| | - Shweta Paulraj
- Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Dongliang Wang
- Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Danning Huang
- Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Abirami Sivapiragasam
- Department of Hematology-Oncology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
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Expression pattern analysis and drug differential sensitivity of cancer-associated fibroblasts in triple-negative breast cancer. Transl Oncol 2020; 14:100891. [PMID: 33069102 PMCID: PMC7563008 DOI: 10.1016/j.tranon.2020.100891] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/29/2020] [Accepted: 09/21/2020] [Indexed: 12/18/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has the characteristics of a complex molecular landscape, aggressive or high proliferation leading to poor prognosis, and behavioral heterogeneity. The purpose of the present study was to determine the spatiotemporal expression of α-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs) at histological level in 4T1 tumors and to predict the sensitivity to 138 drugs in patients with TNBC according to α-SMA expression. The quantitative results of fibrosis showed that the volume of 4T1 tumors correlated positively with the area of tumor fibrosis. Furthermore, we divided 4T1 tumors according to the degree of fibrosis and characterized the molecular characteristics of the four regions. Finally, the difference in the signaling pathways and sensitivity to 138 drugs was analyzed in patients with TNBC according to α-SMA expression combined with The Cancer Genome Atlas (TCGA) database. The myogenesis, TGF-β, and Notch signaling pathways were upregulated and the patients with TNBC were significantly differentially sensitive to 25 drugs. The results of in vivo experiments showed that the inhibitory effect of embelin on 4T1 tumors with high α-SMA expression was greater than that on 4TO7 tumors with low α-SMA expression. At the same time, embelin significantly decreased α-SMA and PDGFRA expression in 4T1 tumors compared with the control group. Our findings add to understanding of CAF distribution in the 4T1 tumor microenvironment and its possible role in treating cancer.
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