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Research Articles: Therapeutics, Targets, and Development

Bisphenol A facilitates bypass of androgen ablation therapy in prostate cancer

¹ Department of Cell and Cancer Biology, ² Department of Environmental Health, ³ Rieveschl Laboratories for Mass Spectrometry, Department of Chemistry, ⁴ Department of Surgery/Shriners Hospital for Children, ⁵ Center for Environmental Genetics, and ⁶ University of Cincinnati Cancer Center, University of Cincinnati College of Medicine, Cincinnati, Ohio

Requests for reprints: Karen E. Knudsen, Department of Cell and Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, 3125 Eden Avenue, ML 0521, Cincinnati, OH 45267-0521. Phone: 513-558-7371; Fax: 513-558-4454. E-mail: Karen.Knudsen{at}uc.edu

Abstract

Prostatic adenocarcinomas depend on androgen for growth and survival. First line treatment of disseminated disease exploits this dependence by specifically targeting androgen receptor function. Clinical evidence has shown that androgen receptor is reactivated in recurrent tumors despite the continuance of androgen deprivation therapy. Several factors have been shown to restore androgen receptor activity under these conditions, including somatic mutation of the androgen receptor ligand-binding domain. We have shown previously that select tumor-derived mutants of the androgen receptor are receptive to activation by bisphenol A (BPA), an endocrine-disrupting compound that is leached from polycarbonate plastics and epoxy resins into the human food supply. Moreover, we have shown that BPA can promote cell cycle progression in cultured prostate cancer cells under conditions of androgen deprivation. Here, we challenged the effect of BPA on the therapeutic response in a xenograft model system of prostate cancer containing the endogenous BPA-responsive AR-T877A mutant protein. We show that after androgen deprivation, BPA enhanced both cellular proliferation rates and tumor growth. These effects were mediated, at least in part, through androgen receptor activity, as prostate-specific antigen levels rose with accelerated kinetics in BPA-exposed animals. Thus, at levels relevant to human exposure, BPA can modulate tumor cell growth and advance biochemical recurrence in tumors expressing the AR-T877A mutation. [Mol Cancer Ther 2006;5(12):3181–90]

Grant support: NIH grant RO1-CA 093404 (K.E. Knudsen), NIH grant RR019900 (to P.A. Limbach), National Institute of Environmental Health Sciences Center for Environmental Genetics core grant E30-ES-06096, and National Institute of Environmental Health Sciences Environmental Mutagenesis and Cancer training grant ES-07250-16 (Y.B. Wetherill and J.K. Hess-Wilson).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Y.B. Wetherill and J.K. Hess-Wilson contributed equally to this work.

Received 5/11/06; revised 9/ 5/06; accepted 10/13/06.