Characterizing and Targeting Androgen Receptor

The androgen receptor (AR) is the principal therapeutic target in prostate cancer. For the past 70 years, androgendeprivation therapy (ADT) has been the major therapeutic focus. However, some patients do not benefit, and those tumorsthat do initially respond to ADT eventually progress. One recently described mechanism of such an effect is growth andsurvival-promoting effects of the AR that are exerted independently of the AR ligands, testosterone anddihydrotestosterone. However, specific ligand-independent AR target genes that account for this effect were not wellcharacterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer growth, is a keyligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels stronglycorrelated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despiteADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Mycsuppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates theanti-growth effects of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Mycfunction and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two criticalproteins in prostate cancer – AR and c-Myc – and demonstrate the potential of AR and c-Myc-directed therapies to improveprostate cancer control. Citation: Gao L, Schwartzman J, Gibbs A, Lisac R, Kleinschmidt R, et al. (2013) Androgen Receptor Promotes Ligand-Independent Prostate Cancer Progressionthrough c-Myc Upregulation. PLoS ONE 8(5): e63563. doi:10.1371/journal.pone.0063563 Editor: Natasha Kyprianou, University of Kentucky College of Medicine, United States of America Received October 30, 2012; Accepted April 2, 2013; Published May 21, 2013 Copyright: 2013 Gao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This publication was made possible with support from the Oregon Clinical and Translational Research Institute, grant number KL2 RR024141 from theNational Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health (JA). This work was alsosupported by the Pacific Northwest Prostate Cancer SPORE/National Cancer Institute (P50CA097186) (JA, PN, IC), the Department of Defense (PC093509) (PSN), aFlight Attendant Medical Research Institute Young Clinical Scientist Award (JA), a Wayne D. Kuni & Joan E. Kuni Foundation Kuni Scholar Award (JA), and aProstate Cancer Foundation Young Investigator Award (JA). With special thanks to Platt Electric, Bruce Burns, and The Burns Family Fund of the OregonCommunity Foundation for their philanthropic support of this work. The funders had no role in study design, data collection and analysis, decision to publish, orpreparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]