The breast cancer promoting effects of bisphenol A (BPA) and its analogues BPF and BPS are associated with aberrations in telomere-telomerase and DNA methylome-wide linked mechanisms

Abstract

The breast cancer promoting effects of bisphenol A (BPA) and its analogues BPF and BPS are associated with aberrations in telomere-telomerase and DNA methylome-wide linked mechanisms Background: Bisphenol A (BPA), an estrogen-like endocrine disruptor used in plastic production, has been associated with development and promotion of breast cancer in multiple animal and cell culture studies, so plastic manufacturers shifted towards the less-studied analogues, BPF and BPS. Telomerase overexpression and DNA methylation aberrations are known to play essential roles in breast cancer development and-or progression. Hence, studying the cancer promoting effects and associated telomere-telomerase- and DNA methylation-linked mechanisms of BPA analogues is timely, particularly in comparison to BPA. Methods: We conducted a dual epidemiological-cell culture approach to test the cancer promoting effects of the three bisphenols and their associated telomere-telomerase and DNA methylation effects. In the epidemiological part, we built on two recruited cohorts: 1) 482 non-breast cancer individuals for whom urinary BPA levels were already measured and peripheral blood samples were stored at -80 0C and 2) 84 breast cancer patients for whom we had access to peripheral blood and tumor and normal adjacent tissue samples. RTL and LINE-1 methylation were measured in both cohorts using quantitative polymerase chain reaction (qPCR) and bisulfite pyrosequencing, respectively. In the cell culture part, we assessed the metabolic activity, viability, cell cycle and migration of breast cancer cells (estrogen receptor-positive (ER-positive): MCF-7 and ER-negative: MDA-MB-231) treated with BPF and BPS ± ER inhibitor (ERI) in comparison to BPA ± ERI. RNA expression, activity of telomerase and DNA (de)methylation enzymes, relative telomere length (RTL) and LINE-1 methylation were quantified. DNA methylome-wide analysis was also evaluated in bisphenol-treated MCF-7 cells, and compared to clinical data on 595 ER-positive breast cancer ti