title: Unique bisphenol A transcriptome in prostate cancer: novel effects on ERbeta expression that correspond to androgen receptor mutation status.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  Our goal was to determine the mechanism of BPA action in cancer cells carrying BPA-responsive AR mutants.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cell and Cancer Biology, University of Cincinnati College of Medicine, Ohio 45267-0521, USA.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Hess-Wilson
authors.forename: Siobhan L
authors.initials: SL
authors.lastname: Webb
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Daly
authors.forename: Yuet-Kin
authors.initials: YK
authors.lastname: Leung
authors.forename: Joanne
authors.initials: J
authors.lastname: Boldison
authors.forename: Clay E S
authors.initials: CE
authors.lastname: Comstock
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.forename: Shuk-Mei
authors.initials: SM
authors.lastname: Ho
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D001559:Benzhydryl Compounds; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010636:Phenols / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D013196:Dihydrotestosterone; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D010636:Phenols; D011944:Receptors, Androgen; C006780:bisphenol A; D000098826:Bisphenol A Compounds