Expression of Androgen Receptor Splice Variants in Prostate Cancer Bone Metastases Is Associated With Castration-Resistance and Short Survival

PLoS One. 2011 Apr 28;6(4):e19059. doi: 10.1371/journal.pone.0019059.

Abstract

Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.

Methodology/principal findings: Hormone-naïve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.

Conclusions/significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Bone Neoplasms / diagnosis
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary*
  • Cell Cycle / genetics
  • Cell Nucleus / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Ligands
  • Male
  • Middle Aged
  • Orchiectomy*
  • Prognosis
  • Prostate / cytology
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / surgery*
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Survival Analysis

Substances

  • Ligands
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Androgen