- Full (HTML) - Full (PDF) - PubMed:Related Articles - PubMed:Citation - Cited in PMC - Purchase This Issue

Janet K. Hess-Wilson,¹ Siobhan L. Webb,¹ Hannah K. Daly,¹ Yuet-Kin Leung,² Joanne Boldison,¹ Clay E.S. Comstock,¹ Maureen A. Sartor,^2,3 Shuk-Mei Ho,^2,3,4 and Karen E. Knudsen^1,3,4

¹Department of Cell and Cancer Biology, ²Department of Environmental Health, ³Center for Environmental Genetics, and ⁴UC Barrett Cancer Center, ⁵University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

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 (ERβ) 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 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.

Key words: androgen receptor, endocrine disruptor, microarray, prostatic adenocarcinoma, xenoestrogen. Environ Health Perspect 115:1646–1653 (2007) . doi:10.1289/ehp.10283 available via http://dx.doi.org/ [Online 23 August 2007]

Address correspondence to K.E. Knudsen, University of Cincinnati College of Medicine, Department of Cell and Cancer Biology, Vontz Center for Molecular Studies, 3125 Eden Ave., ML0521, Cincinnati, OH 45267-0521 USA. Telephone: (513) 558-7371. Fax: (513) 558-4454. E-mail: Karen.Knudsen@UC.edu

We thank S. Khan, E. Knudsen, A. Puga, and all members of both Knudsen laboratories for critical ongoing discussions and insight.

This work was supported by National Institutes of Health grants ES93404 and CA099996 (to K.E.K.) , National Institute of Environmental Health Sciences (NIEHS) Center for Environmental Genetics core grant E30-ES-06096 and NIEHS Environmental Mutagenesis and Cancer training grant ES-07250-16 (J.K.H-W) .

The authors declare they have no competing financial interests.

Received 20 March 2007 ; accepted 23 August 2007.