Article

Bisphenol A Induces Gene Expression Changes and Proliferative Effects through GPER in Breast Cancer Cells and Cancer-Associated Fibroblasts

Department of Pharmaco-Biology, University of Calabria, Rende, Italy.
Environmental Health Perspectives (Impact Factor: 7.98). 05/2012; 120(8):1177-82. DOI: 10.1289/ehp.1104526
Source: PubMed

ABSTRACT

Background: Bisphenol A (BPA) is the principal constituent of baby bottles, reusable water bottles, metal cans, and plastic food containers. BPA exerts estrogen-like activity by interacting with the classical estrogen receptors (ERα and ERβ) and through the G protein-coupled receptor (GPR30/GPER). In this regard, recent studies have shown that GPER was involved in the proliferative effects induced by BPA in both normal and tumor cells.
Objectives: We studied the transduction signaling pathways through which BPA influences cell proliferation and migration in human breast cancer cells and cancer-associated fibroblasts (CAFs).
Methods and results: We used as a model system SKBR3 breast cancer cells and CAFs that lack the classical ERs. Specific pharmacological inhibitors and gene-silencing procedures were used to show that BPA induces the expression of the GPER target genes c-FOS, EGR-1, and CTGF through the GPER/EGFR/ERK transduction pathway in SKBR3 breast cancer cells and CAFs. Moreover, we observed that GPER is required for growth effects and migration stimulated by BPA in both cell types.
Conclusions: Results indicate that GPER is involved in the biological action elicited by BPA in breast cancer cells and CAFs. Hence, GPER-mediated signaling should be included among the transduction mechanisms through which BPA may stimulate cancer progression.

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    • "BPA has been detected in the human placenta (Schonfelder et al., 2002), cord blood (Wan et al., 2010), amitotic fluid (Ikezuki et al., 2002; Yamada et al., 2002), fetal liver (Cao et al., 2012) and breast milk (Sun et al., 2004), making exposure of human neonates and infants a very real concern. According to studies, BPA is estrogen mimic compound resulted in an array of health impacts including prostate and breast cancer (Prins et al., 2008; Pupo et al., 2012). The adverse effects of BPA are largely related to its estrogenic activity (Hiroi et al., 1999; Kurosawa et al., 2002). "
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    • "As it concerns breast malignancy, the role exerted by GPER should be carefully considered owing to its ability to bind not only estrogens but also ER antagonists such as 4-hydroxytamoxifen (OHT) and ICI 182,780, which elicit stimulatory effects particularly in ER-negative cancer cells (Filardo et al., 2000;Lappano et al., 2014;Pandey et al., 2009;Revankar et al., 2005). In addition, GPER signaling is activated by many ER ligands, including natural estrogens and environmental contaminants (Albanito et al., 2015;Maggiolini et al., 2004;Pupo et al., 2012;Thomas and Dong, 2006). It is worthy of noting that we recently identified a compound, named MIBE, that exhibits the peculiar feature of acting as an antagonist ligand of both GPER and ER in breast cancer cells (Lappano et al., 2012a). "
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