Title: Bisphenol A facilitates bypass of androgen ablation therapy in prostate cancer.
Authors: Wetherill, Yelena B; Hess-Wilson, Janet K; Comstock, Clay E S; Shah, Supriya A; Buncher, C Ralph; Sallans, Larry; Limbach, Patrick A; Schwemberger, Sandy; Babcock, George F; Knudsen, Karen E
Published In Mol Cancer Ther, (2006 Dec)
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.
PubMed ID: 17172422
MeSH Terms: Adenocarcinoma/drug therapy*; Adenocarcinoma/pathology; Androgen Receptor Antagonists*; Androgens/metabolism; Animals; Benzhydryl Compounds; Cell Growth Processes/drug effects; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Nude; Phenols/pharmacology*; Prostatic Neoplasms/drug therapy*; Prostatic Neoplasms/pathology; Xenograft Model Antitumor Assays