AR Variant ARv 567 es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate Cancer 1 , 2

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 is one of the two AR variants frequently found in human CRPC xenografts and metastases. Herein, we developed a probasin (Pb) promoter–driven AR transgenic mouse, Pb-AR, to evaluate the role of AR in both autonomous prostate growth and progression to CRPC. We found that expression of AR 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 could induce tumorigenesis de novo and signifies the critical role of AR-Vs in CRPC. Thus, the Pb-AR mouse could provide a novel model in which the role of AR variants in prostate cancer progression can be examined. Neoplasia (2013) 15, 1009–1017 Introduction Patients with castration-resistant prostate cancer (CRPC) have an average survival time of 16 to 18 months from identification of recurrence [1–3]. Despite intensive investigation, treatment resistance of CRPC remains a significant clinical challenge, as the underlying mechanisms are still not fully understood. Persistence of intratumoral androgens [3–6], activation of alternate signaling pathways that could enhance androgen receptor (AR) activity in the presence of lower levels of androgen [7–11], and overexpression of AR that could promote sensitivity to low levels of ligand are all proposed mechanisms for the development of CRPC. Recently, the discovery of constitutively active AR splice variants (AR-Vs) adds credence to the idea that continued signaling through the AR plays a strong role in the development of CRPC [12–15]. The AR-Vs have different structures with each lacking portions of the ligand-binding domain [16–21]. Functionally, these truncated Abbreviations: AR, androgen receptor; AR-FL, AR full length; AR-Vs, androgen receptor splice variants; AR, AR variant with exons 5, 6, and 7 skipped; CRPC, castration-resistant prostate cancer; EMT, epithelial to mesenchymal transition; GSEA, gene set enrichment analysis; GU, genitourinary; Pb, probasin; PIN, prostatic intraepithelial neoplasia; RQ, relative quantification; Tg, transgenic; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling; Ube2c, murine E2 ubiquitin-conjugating enzyme; Wt, wild type Address all correspondence to: Stephen Plymate, MD, Harborview Medical Center, 325 9th Avenue, Box 359625, Seattle, WA 98104. E-mail: splymate@u.washington.edu This work was supported by the National Cancer Institute Pacific Northwest Prostate Cancer Specialized Program of Research Excellence (SPORE; 2 P50 CA 097186-06 Project 4), PO1 CA85859, P01 CA163227, US Army Medical Research and Materiel Command Prostate Cancer Research Program (W81XWH-11-1-0551), Department of Veterans Affairs, and Prostate Cancer Foundation to S.R.P. This article refers to supplementary materials, which are designated by Tables W1 and W2 and Figures W1 to W3 and are available online at www.neoplasia.com. Received 5 April 2013; Revised 17 June 2013; Accepted 24 June 2013 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.13784 www.neoplasia.com Volume 15 Number 9 September 2013 pp. 1009–1017 1009