Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance

Cancer Res. 2008 Jul 1;68(13):5469-77. doi: 10.1158/0008-5472.CAN-08-0594.

Abstract

The standard systemic treatment for prostate cancer (PCa) is androgen ablation, which causes tumor regression by inhibiting activity of the androgen receptor (AR). Invariably, PCa recurs with a fatal androgen-refractory phenotype. Importantly, the growth of androgen-refractory PCa remains dependent on the AR through various mechanisms of aberrant AR activation. Here, we studied the 22Rv1 PCa cell line, which was derived from a CWR22 xenograft that relapsed during androgen ablation. Three AR isoforms are expressed in 22Rv1 cells: a full-length version with duplicated exon 3 and two truncated versions lacking the COOH terminal domain (CTD). We found that CTD-truncated AR isoforms are encoded by mRNAs that have a novel exon 2b at their 3' end. Functionally, these AR isoforms are constitutively active and promote the expression of endogenous AR-dependent genes, as well as the proliferation of 22Rv1 cells in a ligand-independent manner. AR mRNAs containing exon 2b and their protein products are expressed in commonly studied PCa cell lines. Moreover, exon 2b-derived species are enriched in xenograft-based models of therapy-resistant PCa. Together, our data describe a simple and effective mechanism by which PCa cells can synthesize a constitutively active AR and thus circumvent androgen ablation.

Publication types

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

MeSH terms

  • Alternative Splicing / physiology*
  • Animals
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Base Sequence
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm / genetics*
  • Exons*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Molecular Sequence Data
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics*
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism*
  • Transfection
  • Transplantation, Heterologous

Substances

  • AR protein, human
  • Antineoplastic Agents, Hormonal
  • Protein Isoforms
  • Receptors, Androgen