Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy

Oncotarget. 2014 Mar 30;5(6):1646-56. doi: 10.18632/oncotarget.1802.

Abstract

Upregulation of constitutively-active androgen receptor splice variants (AR-Vs) has been implicated in AR-driven tumor progression in castration-resistant prostate cancer. To date, functional studies of AR-Vs have been focused mainly on their ability to regulate gene expression independent of the full-length AR (AR-FL). Here, we showed that AR-V7 and ARv567es, two major AR-Vs, both facilitated AR-FL nuclear localization in the absence of androgen and mitigated the ability of the antiandrogen enzalutamide to inhibit AR-FL nuclear trafficking. AR-V bound to the promoter of its specific target without AR-FL, but co-occupied the promoter of canonical AR target with AR-FL in a mutually-dependent manner. AR-V expression attenuated both androgen and enzalutamide modulation of AR-FL activity/cell growth, and mitigated the in vivo antitumor efficacy of enzalutamide. Furthermore, ARv567es levels were upregulated in xenograft tumors that had acquired enzalutamide resistance. Collectively, this study highlights a dual function of AR-Vs in mediating castration resistance. In addition to trans-activating target genes independent of AR-FL, AR-Vs can serve as a "rheostat" to control the degree of response of AR-FL to androgen-directed therapy via activating AR-FL in an androgen-independent manner. The findings shed new insights into the mechanisms of AR-V-mediated castration resistance and have significant therapeutic implications.

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*
  • Animals
  • Apoptosis / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Chromatin Immunoprecipitation
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasms, Hormone-Dependent / drug therapy
  • Neoplasms, Hormone-Dependent / genetics*
  • Neoplasms, Hormone-Dependent / pathology
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / pharmacology
  • Promoter Regions, Genetic / genetics
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Protein Isoforms
  • Protein Transport / drug effects
  • RNA Splicing / genetics*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Androgen / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Subcellular Fractions
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • AR protein, human
  • Androgens
  • MDV 3100
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Androgen
  • Phenylthiohydantoin