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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Unique bisphenol A transcriptome in prostate cancer: novel effects on ERbeta expression that correspond to androgen receptor mutation status.

Authors: Hess-Wilson, Janet K; Webb, Siobhan L; Daly, Hannah K; Leung, Yuet-Kin; Boldison, Joanne; Comstock, Clay E S; Sartor, Maureen A; Ho, Shuk-Mei; Knudsen, Karen E

Published In Environ Health Perspect, (2007 Nov)

Abstract: Prostatic 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.Our goal was to determine the mechanism of BPA action in cancer cells carrying BPA-responsive AR mutants.The 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).BPA and DHT elicited distinct transcriptional signatures in prostate cancer cells expressing the BPA-responsive mutant AR-T877A. BPA dramatically attenuated estrogen receptor beta (ERbeta) expression; this finding was specific to prostate tumor cells in which BPA induces cellular proliferation.BPA 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 ERbeta. Since ERbeta 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 ERbeta in the proliferative response to BPA will establish the contribution of this event to adverse effects associated with human exposure.

PubMed ID: 18007998 Exiting the NIEHS site

MeSH Terms: Adenocarcinoma/genetics; Adenocarcinoma/metabolism*; Benzhydryl Compounds; Cell Line, Tumor; Dihydrotestosterone/pharmacology; Down-Regulation; Estrogen Receptor beta/genetics; Estrogen Receptor beta/metabolism*; Estrogens, Non-Steroidal/pharmacology*; Gene Expression Profiling*; Gene Expression Regulation, Neoplastic; Humans; Male; Mutation*; Oligonucleotide Array Sequence Analysis; Phenols/pharmacology*; Prostatic Neoplasms/genetics; Prostatic Neoplasms/metabolism*; Receptors, Androgen/genetics*; Receptors, Androgen/metabolism

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