title: Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant.
abstract: Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98104, USA.
authors.forename: Shihua
authors.initials: S
authors.lastname: Sun
authors.forename: Cynthia C T
authors.initials: CC
authors.lastname: Sprenger
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Kathleen
authors.initials: K
authors.lastname: Haugk
authors.forename: Kathryn
authors.initials: K
authors.lastname: Soriano
authors.forename: Elahe A
authors.initials: EA
authors.lastname: Mostaghel
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Page
authors.forename: Ilsa M
authors.initials: IM
authors.lastname: Coleman
authors.forename: Holly M
authors.initials: HM
authors.lastname: Nguyen
authors.forename: Huiying
authors.initials: H
authors.lastname: Sun
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D012326:RNA Splicing; D011944:Receptors, Androgen / Q000235:genetics* / Q000502:physiology; D014183:Transplantation, Heterologous; D000077337:Vorinostat
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D006877:Hydroxamic Acids; D011944:Receptors, Androgen; D000077337:Vorinostat