Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation

PLoS One. 2013 May 21;8(5):e63563. doi: 10.1371/journal.pone.0063563. Print 2013.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgens / pharmacology
  • Azepines / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disease Progression*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Ligands
  • Male
  • Neoplasm Metastasis
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptors, Androgen / metabolism*
  • Triazoles / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics*

Substances

  • (+)-JQ1 compound
  • AR protein, human
  • Androgens
  • Azepines
  • Ligands
  • Proto-Oncogene Proteins c-myc
  • Receptors, Androgen
  • Triazoles