Bisphenol S promotes the cell cycle progression and cell proliferation through ERα-cyclin D-CDK4/6-pRb pathway in...

Bisphenol S (BPS), exhibiting estrogenic activity, has been reported to promote cell proliferation in MCF-7 breast cancer cells; however, the underlying mechanism remains unclear. In this study, BPS (1-100 μM) significantly promoted cell proliferation in ERα positive MCF-7 cells, but not in ERα negative MDA-MB-231 or SK-BR-3 cells, confirming the important role of ERα in BPS-induced cell proliferation. Results of the flow cytometry analysis indicated that 10 μM BPS promoted MCF-7 proliferation by accelerating G₁ to S phase transition of the cell cycle. BPS increased cyclin D1 expression and phospho-retinoblastoma (p-Rb) levels, resulting in the release of E2F transcription factors and the increased expression of downstream cyclin E2 and cyclin A2 genes to promote the cell cycle progression. Moreover, BPS-induced Rb phosphorylation and cell cycle progression were prevented by the ERα inhibitor ICI 182,780 and methylpiperidino pyrazole, as well as cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitor PD 0332991, indicating that the underlying mechanisms involve ERα-dependent pathways but also mediated by cyclin D-CDK4/6. Overall, our result showed, for the first time, that BPS promoted cell cycle progression and cell proliferation through the ERα-cyclin D-CDK4/6-pRb pathway in MCF-7 breast cancer cells. This study provides a novel insight regarding the potential role of cyclin D-CDK4/6-pRb pathway in mediating the proliferative effects of BPS in breast cancer cells.