AR Variant ARv567es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate Cancer

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. AR(v567es) is one of the two AR variants frequently found in human CRPC xenografts and metastases. Herein, we developed a probasin (Pb) promoter-driven AR(v567es) transgenic mouse, Pb-AR(v567es), to evaluate the role of AR(v567es) in both autonomous prostate growth and progression to CRPC. We found that expression of AR(v567es) 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 AR(v567es) could induce tumorigenesis de novo and signifies the critical role of AR-Vs in CRPC. Thus, the Pb-AR(v567es) mouse could provide a novel model in which the role of AR variants in prostate cancer progression can be examined.