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 (ER alpha+/ER beta-) cells. However, it is not clear whether ER expression pattern affects GEN's modulation on CIS's activity. In the present study, breast cancer ER beta knockdown (ER beta KD) MDA-MB-231 (ER alpha-/ER beta+) cell model was established via ER RNAi lentivirus infection. The role of ER 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 ERKD cells exhibited higher sensitivity to both GEN and CIS treatment. GEN and CIS showed synergistic effects only in ER-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 ER-deficient cells. This indicated ER 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 ER alpha-/ER beta- breast cancer cases. ER pathway might be one of the potential targets which elicit GEN's positive effects in ER alpha- breast cancer patients.