title: AR-Q640X, a model to study the effects of constitutively active C-terminally truncated AR variants in prostate cancer cells.
abstract: OBJECTIVE
  A recently identified mechanism allowing prostate cancer (PCa) cells to grow in the absence of androgens is the expression of constitutively active, C-terminally truncated androgen receptor (AR) variants lacking vast parts of the ligand-binding domain. These AR variants termed ARΔLBD are either products of alternative splicing, point mutations leading to premature stop codons or proteolytic cleavage of the AR. Some controversies exist about the requirement of additional full-length AR for the full transcriptional activity of the ARΔLBD. On basis of a mutated, C-terminally truncated AR termed Q640X, we developed an experimental model for the study of ARΔLBD in PCa cells.
  
  
  METHODS
  Activation of AR-dependent promoters was analyzed by reporter gene assays. Dimerization studies were conducted using a mammalian two-hybrid system.
  
  
  RESULTS
  Although Q640X/Q640X homodimers were able to induce the expression of certain AR target genes, Q640X/AR heterodimers were necessary to activate the full panel of androgen-dependent genes under androgen-deprived conditions.
  
  
  CONCLUSIONS
  The following study supports the hypothesis that castration-resistant prostate cancer (CRPC) cells are able to activate specific androgen-dependent genes by selective modulation of the ratio between ARΔLBD and their putative dimerization partners like the full-length AR or other ARΔLBD in the absence of androgens. The present data suggest that AR-mutant Q640X is a powerful experimental tool for the functional analysis of ARΔLBD in CRPC.
authors.affiliation: Department of Urology, Research Laboratory, University of Ulm, Prittwitzstrasse 43, 89075, Ulm, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Streicher
authors.forename: Friedemann
authors.initials: F
authors.lastname: Zengerling
authors.forename: Martin
authors.initials: M
authors.lastname: Laschak
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weidemann
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Schrader
authors.forename: Florian
authors.initials: F
authors.lastname: Jentzmik
authors.forename: Mark
authors.initials: M
authors.lastname: Schrader
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Cronauer
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000728:Androgens / Q000235:genetics / Q000502:physiology; D002369:Castration; D045744:Cell Line, Tumor; D019281:Dimerization; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D011944:Receptors, Androgen / Q000235:genetics* / Q000502:physiology*; D014162:Transfection; D017211:Treatment Failure
chemical_list: D000728:Androgens; D011944:Receptors, Androgen