title: AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer.
abstract: Androgen deprivation therapy remains the primary treatment modality for patients with metastatic prostate cancer but is uniformly marked by progression to castration-resistant prostate cancer (CRPC) after a period of regression. Continued activation of androgen receptor (AR) signaling is attributed as one of the most important mechanisms underlying failure of therapy. Recently, the discovery of constitutively active AR splice variants (AR-Vs) adds more credence to this idea. Expression of AR-Vs in metastases portends a rapid progression of the tumor. However, the precise role of the AR-Vs in CRPC still remains unknown. ARv567es is one of the two AR variants frequently found in human CRPC xenografts and metastases. Herein, we developed a probasin (Pb) promoter-driven ARv567es transgenic mouse, Pb-ARv567es, to evaluate the role of ARv567es in both autonomous prostate growth and progression to CRPC. We found that expression of ARv567es in the prostate results in epithelial hyperplasia by 16 weeks and invasive adenocarcinoma is evident by 1 year of age. The underlying genetic cellular events involved a cell cycle-related transcriptome and differential expression of a spectrum of genes that are critical for tumor initiation and progression. These findings indicate that ARv567es could induce tumorigenesis de novo and signifies the critical role of AR-Vs in CRPC. Thus, the Pb-ARv567es mouse could provide a novel model in which the role of AR variants in prostate cancer progression can be examined.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sprenger
authors.forename: Shihua
authors.initials: S
authors.lastname: Sun
authors.forename: Kathryn Soriano
authors.initials: KS
authors.lastname: Epilepsia
authors.forename: Kathleen
authors.initials: K
authors.lastname: Haugk
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Stephen
authors.initials: S
authors.lastname: Plymate
mesh_terms: D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics; D009919:Orchiectomy; D011401:Promoter Regions, Genetic; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000727:Androgen-Binding Protein; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D020033:Protein Isoforms; D011944:Receptors, Androgen; C027519:probasin
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