Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway

Abstract

Abstract. Various endocrine disrupting chemicals (EDCs) are exogenous compounds found in the environment and have the potential to interfere with the endocrine system and hormonal regulation. Among EDCs, bisphenol A (BPA) and 1,1,1-trichloro-2,2-bis(4-methoxyphenol)-ethane [methoxychlor (MXC)] have estrogenic activity resulting in a variety of dysfunctions in the E2-mediated response by binding to estrogen receptors (ERs), causing human health problems such as abnormal reproduction and carcinogenesis. In this study, we investigated the effects of BPA and MXC on cell proliferation facilitated by ER signaling in human breast cancer cells. MCF-7 cells are known to be ERα-positive and to be a highly E2-responsive cancer cell line; these cells are, therefore, a useful in vitro model for detecting estrogenic activity in response to EDCs. We evaluated cancer cell proliferation following BPA and MXC treatment using an MTT assay. We analyzed alterations in the expression of genes associated with the cell cycle in MCF-7 cells by semi-quantitative reverse-transcription PCR following treatment with BPA or MXC compared to EtOH. To determine whether BPA and MXC stimulate cancer cell growth though ER signaling, we co-treated the cells with agonists (propyl pyrazoletriol, PPT; and diarylpropionitrile, DPN) or an antagonist (ICI 182,780) of ER signaling and reduced ERα gene expression via siRNA in MCF-7 cells before treatment with EDCs. These studies confirmed the carcinogenicity of EDCs in vitro. As a result, BPA and MXC induced the cancer cell proliferation by the upregulation of genes that promote the cell cycle and the downregulation of anti-proliferative genes, especially ones affecting the G1/S transition via ERα signaling. These collective results confirm the carcinogenicity of these EDCs in vitro. Further studies are required to determine whether EDCs promote carcinogenesis in vivo.

LncRNA HOTAIR: A master regulator of chromatin dynamics and cancer

“…Endocrine disruptors interact with hormone receptors even at very low concentrations and interfere with hormone signaling affecting various hormonally regulated processes including reproduction and development [67, 85, 86]. Endocrine disruptors are also capable of inducing aberrant and altered gene expression [85, 86].…”

“…Endocrine disruptors interact with hormone receptors even at very low concentrations and interfere with hormone signaling affecting various hormonally regulated processes including reproduction and development [67, 85, 86]. Endocrine disruptors are also capable of inducing aberrant and altered gene expression [85, 86]. Exposure to estrogenic endocrine disruptors such as bisphenol-A (BPA) and synthetic estrogens such as diethylstilbestrol (DES) alters uterine HOX gene expression and induces developmental changes in the female reproductive tract [87–89].…”

Effects of bisphenol compounds on the growth and epithelial mesenchymal transition of MCF-7 CV human breast cancer cells

“…Meanwhile, BPA has long been a health concern associated with serious and chronic conditions due to its potency as a crucial EDC having an estrogenic effect in the body and its widespread exposure [ 7,9–10 ] . Specifically, BPA was reported to have the potential to increase cancer risk [ 11 ] and to have cell proliferation effects in estrogen-dependent breast and ovarian cancer cells as in case of endogenous estrogen, 17β-estradiol (E2), which has been reported to be closely linked to the pathogenesis of some cancers occurring in the reproductive organs [ 9,12–13 ] . In animal experiments, BPA forced breast and prostate cells to be predisposed to cancer [ 14–15 ] .…”

Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo

“…EDCs interact with hormone receptors even at very low concentrations and interfere with hormone signaling affecting various hormonally regulated processes including reproduction and development (Brown and Lamartiniere 1995; Calle et al 1996; BLOCK et al 2000; Munoz-de-Toro et al 2005; Susiarjo et al 2007; Adamsson et al 2008; Baba et al 2009; Doherty et al 2010a; Mahoney and Padmanabhan 2010; Gibert et al 2011; Wolstenholme et al 2012; Xu et al 2012). Chronic or acute exposure to EDCs results in harmful health effects including birth defects, diabetes, cancers, reproductive problems, early puberty, and obesity (Hwang et al 2008; Jacobs et al 2008; Nakanishi 2008; Navas and Segner 2008; Phillips and Foster 2008; Schoeters et al 2008; Wohlfahrt-Veje et al 2009; Grun 2010; Casals-Casas and Desvergne 2011; Lee et al 2012; Fenichel et al 2013; Vuorinen et al 2013). EDCs may induce aberrant and altered gene expression.…”