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


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.

Download full-text


Available from: Camillo Rosano
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bisphenol A (BPA) is an endocrine disrupting compound widely spread in our living environment. It is a contaminant with increasing exposure to it and exerts both toxic and estrogenic effects on mammalian cells. Due to the limited information concerning the effect of BPA on the liver, the present study was designed to assess hepatic tissue injury induced by early life exposure to BPA in female rat offspring. Rat dams (n = 9) were gavaged with 0.5 and 50 mg of BPA/kg b.w./day throughout lactation until weaning. The sham group received olive oil for the same duration while the control group did not receive any injection. The liver tissue was collected from female pups at different pubertal periods (PND50, 90 and 110) to evaluate oxidative stress biomarkers, extent of DNA damage and histopathological changes. Our results indicated that early life exposure to BPA significantly increased oxidative/nitrosative stress, decreased antioxidant enzyme activities, induced DNA damage and chronic severe inflammation in the hepatic tissue in a time dependent manner. These data suggested that BPA causes long-term adverse effects on the liver, which leads to deleterious effects in the liver of female rat offspring.
    Full-text · Article · Aug 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Estrogens regulate numerous pathophysiological processes mainly binding to and activating the estrogen receptor (ER)α and ERβ. Increasing evidence has recently demonstrated that the G protein-coupled receptor 30 (GPR30/GPER) is also involved in diverse biological responses to estrogens in normal and cancer cells. The classical ER and GPER share several features, including the ability to bind to identical compounds, nevertheless some ligands exhibit opposed activity through these receptors. Worthy, the availability of selective agonists and antagonists of GPER has shown certain differential roles elicited by GPER respect to ER. Here, we provide evidence on the molecular mechanisms through which a calixpyrrole derivative acts as a GPER antagonist in different model systems, like breast tumor cells and cancer-associated fibroblasts (CAFs) obtained from breast cancer patients. Our data may open new perspectives toward the development of a further class of selective GPER ligands in order to better dissect the role exerted by this receptor in different pathophysiological conditions. Moreover, calixpyrrole derivatives may be considered in future anticancer strategies targeting GPER in cancer cells. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Jul 2015 · Disease Models and Mechanisms
  • Source
    • "In recent years, receptor-mediated and cell signaling-mediated mechanisms have gained considerable concern and gradually became the main theory to interpret the HCR at molecular level (Calabrese, 2013b). For instance, the BPA-induced cell proliferation at low concentration results from a feedback stimulatory loop by activating the G protein-coupled receptor (GPCRs)-mediated signaling pathway (Bouskine et al., 2009; Pupo et al., 2012; Sheng et al., 2013). The receptor-mediated hormetic mechanism can be divided into three modes: (Calabrese, 2013b) 1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The hormesis characterized by low-concentration stimulation and high-concentration inhibition has gained significant interest over the past decades. Some organic solvents and ionic liquids (ILs) have hormetic concentration responses (HCR) to bioluminescence such as firefly luciferase and Vibrio qinghaiensis sp.-Q67. In this study, we determine the effects of 1-alkyl-3-methylimidazolium chlorine ILs ([Cnmim]Cl, n=2, 4, 6, 8, 10 and 12) to firefly luciferase in order to verify the mechanism of hormesis. The luminescence inhibition toxicity tests show that the stimulation effects of [C8mim]Cl and [C10mim]Cl are obvious, [C6mim]Cl and [C12mim]Cl are minor, and [C2mim]Cl and [C4mim]Cl are rare. The enzyme kinetics show that [C8mim]Cl and [C10mim]Cl are the competitive inhibitors with ATP while [C2mim]Cl and [C4mim]Cl are the noncompetitive ones. Molecular dynamics simulation results reveal that imidazolium rings of [C8mim] and [C10mim] locate at the entrance of luciferin pocket which is adjacent to AMP pocket, while alkyl-chains insert into the bottom of the luciferin pocket. Combining the results from inhibition test, kinetics assay and molecular simulation, we can deduce that occupying AMP pocket by imidazolium ring is responsible for hormetic stimulation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Mar 2015 · Chemosphere
Show more