Unique Bisphenol A Transcriptome in Prostate Cancer: Novel Effects on ERβ Expression That Correspond to Androgen Receptor Mutation Status

Abstract

BackgroundProstatic adenocarcinomas are dependent on androgen receptor (AR) activity for growth and progression, and therapy for disseminated disease depends on ablation of AR activity. Recurrent tumors ultimately arise wherein AR has been re-activated. One mechanism of AR restoration is via somatic mutation, wherein cells containing mutant receptors become susceptible to activation by alternative ligands, including bisphenol A (BPA). In tumors with specific AR mutations, BPA promotes therapeutic bypass, suggesting significant negative impact to the clinical management of prostate cancer.ObjectiveOur goal was to determine the mechanism of BPA action in cancer cells carrying BPA-responsive AR mutants.MethodsThe molecular signature of BPA activity in prostate cancer cells harboring mutant AR was delineated via genetic microarray analysis. Specificity of BPA action was assessed by comparison with the molecular signature elicited by dihydrotestosterone (DHT).ResultsBPA and DHT elicited distinct transcriptional signatures in prostate cancer cells expressing the BPA-responsive mutant AR-T877A. BPA dramatically attenuated estrogen receptor beta (ERβ) expression; this finding was specific to prostate tumor cells in which BPA induces cellular proliferation.ConclusionsBPA induces a distinct gene expression signature in prostate cancer cells expressing somatic AR mutation, and a major molecular consequence of BPA action is down-regulation of ERβ. Since ERβ functions to antagonize AR function and AR-dependent proliferation, these findings reveal a novel mechanism by which BPA likely regulates cellular proliferation. Future investigation directed at dissecting the importance of ERβ in the proliferative response to BPA will establish the contribution of this event to adverse effects associated with human exposure.

Bisphenol A impairs estradiol‐induced protective effects against DLD‐1 colon cancer cell growth

“…BPA is known to harbor estrogenic activity: this compound is a weak ligand of both ERa and ERb (13) and moderately stimulates E2-independent proliferation in ERa-containing breast cancer cells and in ERaoverexpressed HeLa cells, a cervix carcinoma cell line (16)(17)(18)(19). To our knowledge, scarce and conflicting investigations have been aimed at dissecting the role played by ERb in the estrogenic activity of BPA (14,20).…”

Scientific Opinion on Bisphenol A: evaluation of a study investigating its neurodevelopmental toxicity, review of recent scientific literature on its toxicity and advice on the Danish risk assessment of Bisphenol A

“…The same BPA concentration has been suggested to interfere with gene expression in the differentiation of embryonic stem cells of monkeys . A cell-specific effect of BPA at a low concentration (1 nM) was reported in androgen receptor mutated prostate cancer cells: BPA induced a pattern of gene expression partly overlapping with that of dihydrotestosterone, specifically down-regulating oestrogen receptor β (Hess-Wilson et al, 2007). Effects on the immune system Miao et al (2008) studied the immunological effects resulting from a continuous prenatal and postnatal (until PND 30) oral exposure to BPA (4, 40 and 400 mg/kg b.w./day; gavage) in F344 rats.…”

Bisphenol A may reduce the efficacy of androgen deprivation therapy in prostate cancer

“…Multiple lines of evidence indicate that the key event resulting in BPA-facilitated therapeutic bypass of prostate cancer cells is the binding to and activation of tumor-derived mutant ARs by BPA, resulting in BPA:AR complex-mediated cellular proliferation [28][29][30]46].…”

“…Activation of tumor-derived AR mutants has been identified as a key event; however, the precise mechanism of AR proliferative regulation is, itself, poorly understood. Experiments comparing the transcriptional signature profiles of BPA-treated and DHT-treated prostate cancer cells have attempted to elucidate the genetic mechanisms of BPA-mediated proliferation and have confirmed BPAmediated induction of AR target genes [46]. Interestingly, BPA treatment also resulted in downregulation of estrogen receptor beta (ERb), not seen with DHT [46].…”

“…Experiments comparing the transcriptional signature profiles of BPA-treated and DHT-treated prostate cancer cells have attempted to elucidate the genetic mechanisms of BPA-mediated proliferation and have confirmed BPAmediated induction of AR target genes [46]. Interestingly, BPA treatment also resulted in downregulation of estrogen receptor beta (ERb), not seen with DHT [46]. This observation is significant because ERb is thought to be required for AR-mediated proliferation of androgen-dependent prostate cancer cells [48,49].…”