ERβ modulates genistein’s cisplatin-enhancing activities in breast cancer MDA-MB-231 cells via P53-independent pathway

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.