Affordable Access

deepdyve-link
Publisher Website

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

Authors
  • Dehm, Scott M
  • Schmidt, Lucy J
  • Heemers, Hannelore V
  • Vessella, Robert L
  • Tindall, Donald J
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Jul 01, 2008
Volume
68
Issue
13
Pages
5469–5477
Identifiers
DOI: 10.1158/0008-5472.CAN-08-0594
PMID: 18593950
Source
Medline
License
Unknown

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.

Report this publication

Statistics

Seen <100 times