Bisphenol A Induces Gene Expression Changes and Proliferative Effects through GPER in Breast Cancer Cells and Cancer-Associated Fibroblasts

BACKGROUND: Bisphenol-A (BPA) is the principal constituent of baby bottles, reusable water bottles, metal cans and plastic food containers. BPA exerts estrogen-like activity interacting with the classical estrogen receptors (ERα and ERβ) and through the G protein-coupled receptor named Gpr30/Gper. In this regard, recent studies have shown that Gper was involved in the proliferative effects induced by BPA in both normal and tumor cells. OBJECTIVES: We studied the transduction signaling pathways through which BPA influences cell proliferation and migration in breast cancer cells and cancer-associated fibroblasts (CAFs). METHODS AND RESULTS: We used as a model system the SKBR3 breast cancer cells and CAFs that lack the classical ERs. Specific pharmacological inhibitors and gene-silencing procedures were used to show that BPA induces the expression of the Gper target genes c-FOS, EGR-1 and CTGF through the Gper/egfr/erk transduction pathway in SKBR3 breast cancer cells and CAFs. Moreover, we demonstrate that Gper is required for the growth effects and migration stimulated by BPA in both cell types. CONCLUSIONS: Our results indicate that Gper is involved in the biological action elicited by BPA in breast cancer cells and CAFs. Hence, Gper-mediated signaling should be included among the transduction mechanisms through which BPA may stimulate cancer progression.