title: Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Hörnberg
authors.forename: Erik Bovinder
authors.initials: EB
authors.lastname: Ylitalo
authors.forename: Sead
authors.initials: S
authors.lastname: Crnalic
authors.forename: Henrik
authors.initials: H
authors.lastname: Antti
authors.forename: Pär
authors.initials: P
authors.lastname: Stattin
authors.forename: Anders
authors.initials: A
authors.lastname: Widmark
authors.forename: Anders
authors.initials: A
authors.lastname: Bergh
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wikström
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000556:secondary*; D002453:Cell Cycle / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D011379:Prognosis; D011467:Prostate / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000601:surgery*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D012333:RNA, Messenger; D011944:Receptors, Androgen