Androgen Receptor Promotes Ligand-Independent Prostate Cancer Progression through c-Myc Upregulation

Lina Gao, Jacob Schwartzman, Angela Gibbs, Robert Lisac, Richard Kleinschmidt, Beth Wilmot, Daniel Bottomly, Ilsa Coleman, Peter Nelson, Shannon McWeeney, Joshi Alumkal

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

The androgen receptor (AR) is the principal therapeutic target in prostate cancer. For the past 70 years, androgen deprivation therapy (ADT) has been the major therapeutic focus. However, some patients do not benefit, and those tumors that do initially respond to ADT eventually progress. One recently described mechanism of such an effect is growth and survival-promoting effects of the AR that are exerted independently of the AR ligands, testosterone and dihydrotestosterone. However, specific ligand-independent AR target genes that account for this effect were not well characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer growth, is a key ligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-growth effects of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer - AR and c-Myc - and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control.

Original languageEnglish (US)
Article numbere63563
JournalPloS one
Volume8
Issue number5
DOIs
StatePublished - May 21 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Gao, L., Schwartzman, J., Gibbs, A., Lisac, R., Kleinschmidt, R., Wilmot, B., Bottomly, D., Coleman, I., Nelson, P., McWeeney, S., & Alumkal, J. (2013). Androgen Receptor Promotes Ligand-Independent Prostate Cancer Progression through c-Myc Upregulation. PloS one, 8(5), [e63563]. https://doi.org/10.1371/journal.pone.0063563