Bisphenol A (BPA) Up-regulated Expression Of DNMT1 And DNMT3b In MCF-7 Breast Cancer Cells Through Activation Of ERα

Breast cancer is one of the most common worldwide diseases in women, and usually treated by surgery accompanied by chemotherapy and adjuvant endocrinotherapy. Drug resistance is the major obstacle for successful chemotherapy. Estrogen receptor (ERa) is expressed in approximately 65% of human breast cancer. Increasing evidence has confirmed that ERa (+) tumors are more resistance to chemotherapy than ERa(-) tumors although patients with ERa (+) breast cancer have better prognosis than ER a(-) cancer because of benefitting from endocrine therapy. Aberrant DNA methylation was the first epigenetic mark to be associated with drug resistance. Our previous study and new experimental data have shown that ERa could enhance the DNMT1 transcriptional activity by directly binding to the DNMT1 promoter in ERa(+) cell lines and increase resistance of breast cancer cells to chemotherapy agent.Bisphenol A (BPA) is a carbon-based synthetic compound that is made into a variety of common consumer goods, such as water bottles, food containers and sports equipment. BPA exhibits hormone-like properties and execute estrogen-like effect. In order to determine whether BPA is able to alter expression of DNMTs through activating ERa and thus increase the drug resistance of ERa(+) breast cancer cells to chemotherapy, the effect of BPA on expression of DNMT1, DNMT3a and DNMT3b and its correlation with response of MCF-7 breast cancer cells to paclitaxel were investigated using real time PCR, Western blot, ChIP and reporter gene system. Our data demonstrated that BPA could increase transcriptional activity of DNMT1, DNMT3a and DNMT3b. BPA exposure increased ERa bindings on the promoters of DNMT1 and DNMT3b genes, but not on the promoter of DNMT3a. Knockdown of ERa partially reversed the enhancement effects of BPA on expression of DNMT1 and DNMT3b, decreased the global genomic methylation level and increased sensitivity of MCf-7 cells to paclitaxel. This work functionally linked BPA, to DNA methlation regulation that may alter drug response of cancer cells and was significant given that BPA is a widely used in common consumer goods.