Bisphenol A facilitates bypass of androgen ablation therapy in prostate cancer.
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.
Wetherill
Yelena B
YB
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, USA.
Hess-Wilson
Janet K
JK
Comstock
Clay E S
CE
Shah
Supriya A
SA
Buncher
C Ralph
CR
Sallans
Larry
L
Limbach
Patrick A
PA
Schwemberger
Sandy
S
Babcock
George F
GF
Knudsen
Karen E
KE
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010636:Phenols / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000098826:Bisphenol A Compounds
D059002:Androgen Receptor Antagonists; D000728:Androgens; D001559:Benzhydryl Compounds; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds