ERβ modulates genistein’s cisplatin-enhancing activities in breast cancer MDA-MB-231 cells via P53-independent pathway
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As one of the typical food-derived phytoestrogens, genistein (GEN) could bind to estrogen receptor (ER) and was reported to be closely related to breast cancer. Our former research showed that GEN interfered with the anti-tumor effects of cisplatin (CIS) in breast cancer MCF-7 (ERα+/ERβ−) cells. However, it is not clear whether ER expression pattern affects GEN’s modulation on CIS’s activity. In the present study, breast cancer ERβ knockdown (ERβKD) MDA-MB-231 (ERα−/ERβ+) cell model was established via ERβ RNAi lentivirus infection. The role of ERβ expression in GEN’s bioeffects on cells’ response to CIS was investigated and was further double-checked by pathway-specific inhibitor PHTPP. Consistent results were harvested through cell viability analysis, cell cycle distribution flow cytometry, TUNEL staining, and expression detection of key biomarkers, Bax, Bcl-2, P21, P53, and cleaved caspase-3. Compared with the control group, PHTPP-treated or ERβKD cells exhibited higher sensitivity to both GEN and CIS treatment. GEN and CIS showed synergistic effects only in ERβ-deficient cells. This effect mainly resulted in G2 phase arresting and apoptosis induction with the upregulation of P21 and Bax/Bcl-2 protein level. Besides, P53 expression was strikingly suppressed in ERβ-deficient cells. This indicated ERβ pathway deficiency might enhance GEN–CIS bioactivity via the downregulation of P53. In summary, our data imply that daily intake of GEN-rich diet could collaborate with CIS anti-tumor treatment in ERα−/ERβ− breast cancer cases. ERβ pathway might be one of the potential targets which elicit GEN’s positive effects in ERα− breast cancer patients.
KeywordsGenistein Cisplatin Breast cancer ERβ Chemotherapy P53-independent
Triple-negative breast cancer
Selective estrogen receptor modulators
This work was supported by the National Natural Science Foundation of China (Grant Number: 81460468); the Youth Science Funding Program of Jiangxi Province (Grant Number: 20142BAB215044) and Nanchang University Innovation Funding Project for Graduate Students (Grant Number: CX2018192).
Compliance with ethical standards
Conflict of interest
All authors declare no potential conflicts of interest.
- 1.Martin HL, Smith L, Tomlinson DC (2014) Multidrug-resistant breast cancer: current perspectives. Breast Cancer Targets Ther 6:1Google Scholar
- 4.Karaayvaz M, Cristea S, Gillespie SM, Patel AP, Mylvaganam R, Luo CC, Specht MC, Bernstein BE, Michor F, Ellisen LW (2018) Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-sEq. Nat Commun 9:3588. https://doi.org/10.1038/s41467-018-06052-0 CrossRefGoogle Scholar
- 5.Li X, Zhang Y, Meisel J, Jiang R, Behera M, Peng L (2018) Validation of the newly proposed American Joint Committee on Cancer (AJCC) breast cancer prognostic staging group and proposing a new staging system using the National Cancer Database. Breast Cancer Res Treatment 1–11Google Scholar
- 7.Elebro K, Borgquist S, Rosendahl AH, Markkula A, Simonsson M, Jirström K, Rose C, Ingvar C, Jernström H (2017) High estrogen receptor β expression is prognostic among adjuvant chemotherapy-treated patients-results from a population-based breast cancer cohort. Clin Cancer Res 23:766–777CrossRefGoogle Scholar
- 24.Tseng TH, Chien MH, Lin WL, Wen YC, Chow JM, Chen CK, Kuo TC, Lee WJ (2017) Inhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21WAF1/CIP1 expression. Environ Toxicol 32:434CrossRefGoogle Scholar
- 27.Sotoca AM, Gelpke MD, Boeren S, Strom A, Gustafsson JA, Murk AJ, Rietjens IM, Vervoort J (2011) Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteom. https://doi.org/10.1074/mcp.M110.002170 Google Scholar
- 40.Rottenberg S, Nygren AOH, Pajic M, Leeuwen FWBV, Heijden IVD, Wetering KVD, Liu X, Visser KED, Gilhuijs KG, Tellingen OV (2007) Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl Acad Sci USA 104:12117–12122CrossRefGoogle Scholar