Low doses of bisphenol A stimulate the proliferation of breast cancer cells via ERK1/2/ERRγ signals

The effects and mechanisms of bisphenol A (BPA) on the development of breast cancer are still not well illustrated. The present study revealed that nanomolar BPA significantly promoted the proliferation of both estrogen receptor (ER) positive (MCF-7) and negative (SkBr3) breast cancer cells, which was confirmed by up regulation of proliferating cell nuclear antigen (PCNA) and Bcl-2. Neither ER alpha. nor G-protein-coupled estrogen receptor (GPER) mediated this effect of BPA because their inhibitors had no effect on the BPA induced cell proliferation. However, silencing of estrogen related receptor gamma (ERR gamma) by its specific siRNA significantly abolished BPA induced proliferation of breast cancer cells, while si-ERR alpha had no similar effect. Moreover, nanomolar BPA up regulated the mRNA and protein levels of ERR gamma and triggered its nuclear translocation via a time dependent manner. Further studies revealed that 10(-8) M BPA obviously increased the phosphorylation of ERK1/2, while had no similar effect on the phosphorylation of JNK and p38 MAPK. Further, PD 98059, the inhibitor of ERK1/2, significantly abolished the EPA induced up regulation of ERR gamma and proliferation of breast cancer cells. Collectively, our results revealed that nanomolar BPA can trigger the proliferation,of breast cancer cells via ERK1/2/ERR gamma signals. Given that nanomolar BPA has been widely detected in human tissues, the clinical relevance of BPA and breast cancer progression should be further investigated. (C) 2015 Elsevier Ltd. All rights reserved.