SAT-725 Alterations in the Phenotype and Epigenomic Landscape of Luminal Breast Cancer Following Long-Term Nanomolar Exposure to Bisphenol a (BPA)

摘要

Breast cancer (BCa) is the leading cause of female cancer-related death worldwide. Luminal BCa accounts for at least 70% of all BCa and is characterized by its hormone dependence, particularly to estrogen. Endocrine disruptors may function to exert the pro-tumorigenic effects of estrogen in proxy following environmental exposure. Bisphenol A (BPA) is a ubiquitous endocrine disruptor shown to increase risk towards developing BCa in multiple in vivo mammalian models and in vitro human breast models. Despite this, there is limited information on the phenotypic and epigenetic effects of nanomolar BPA following long-term exposure particularly in the context of BCa stem cell population, which accumulate the ‘cellular insult’ and are likely to pass such information down through epigenetic mechanisms. We hypothesize that BPA affects the epigenome, in part, by altering the regulation of DNA methyltransferases (DNMTs) since BPA disrupts transcriptional and translational regulation of DNMTs in various other tissue types such as the brain, testis and prostate. In this study, MCF7 cells were chronically (>4 weeks) cultured with nanomolar doses of BPA, and subsequently subjected to phenotypic assays and gene expression analysis in monolayer or mammosphere culture. Gene expression analysis revealed a downregulation of DNMT3A and ESR1 following long-term exposure to BPA in mammosphere culture of MCF7 cells, but not in monolayer culture. This is accompanied by alterations in mammosphere morphology, reduction in mammosphere size, an increase in the mammosphere number, and an increase in the CD49f+ population, indicating a positive contribution of BPA to stemness. However, there are no significant changes in proliferation, apoptotic rate, and metastasis in both monolayer and mammosphere culture. Future analysis includes assessment of genome-wide alterations in DNA methylation patterns in these chronically exposed MCF7 mammospheres, as well as identifying estrogen responsiveness, chemotherapeutic response, and self-renewal properties of these cancer cells.