A Snapshot of the Expression Signature of Androgen Receptor Splicing Variants and Their Distinctive Transcriptional Activities

Prostate. 2011 Nov;71(15):1656-67. doi: 10.1002/pros.21382. Epub 2011 Mar 28.

Abstract

Background: The diversity and complexity of the human androgen receptor (AR) splicing variants are well appreciated but not fully understood. The goal of this study is to generate a comprehensive expression signature of AR variants in castration-resistant prostate cancer (CRPC), and to address the relative importance of the individual variants in conferring the castration-resistant phenotype.

Methods: A modified RNA amplification method, termed selective linear amplification of sense RNA, was developed to amplify all AR transcripts containing AR exon 3 in CRPC specimens, which were profiled using tiling expression microarrays. Coding sequences for the AR variants were cloned into expression vectors and assessed for their transcriptional activities. Quantitative RT-PCR was used to determine their in vivo expression patterns in an expanded set of clinical specimens.

Results: In addition to expression peaks in AR intron 3, a novel AR exon, termed exon 9, was discovered. Exon 9 was spliced into multiple novel AR variants. Different AR splicing variants were functionally distinctive, with some demonstrating constitutive activity while others were conditionally active. Conditionally active AR-Vs may activate AR signaling depending on the cellular context. Importantly, AR variant functions did not appear to depend on the full-length AR.

Conclusions: This study provided the first unbiased snapshot of the AR variant signature consisting of multiple AR variants with distinctive functional properties, directly in CRPC specimens. Study findings suggest that the aggregate function of multiple AR variants may confer a castration-resistant phenotype independent of the full-length AR.

Publication types

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

MeSH terms

  • Alternative Splicing
  • Cell Line, Tumor
  • Cloning, Molecular
  • Exons
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Introns
  • Male
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism*
  • Protein Isoforms
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • Receptors, Androgen / biosynthesis*
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Statistics, Nonparametric
  • Transcriptional Activation*

Substances

  • AR protein, human
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Androgen