The Prostate 66:1445 ^1454 (2006) Clusterin Is Not Essential for Androgen-Regulated Involution and Regeneration of the Normal Mouse Prostate Dieter Fink, 1 Ladan Fazli, 1 Bruce Aronow, 3 Martin E. Gleave, 1,2 and Christopher J. Ong 1,2 * 1 The Prostate Centre at VGH,University of British Columbia,Vancouver, British Columbia,Canada 2 Department of Surgery,University of British Columbia,Vancouver, British Columbia,Canada 3 Cincinnati Children’s Hospital Medical Center,Cincinnati,Ohio BACKGROUND. Inhibition of clusterin expression has been shown to enhance the sensitivity of prostate cancer cells to chemo and hormone therapy. Clusterin antisense oligonucleotides (ASOs) are currently in phase II human clinical trials for treatment of hormone refractory prostate cancer. However, the role of clusterin in androgen-regulated involution and regeneration of the normal prostate gland has not been established. METHODS. Prostate involution and regeneration was examined in clusterin-deficient mice undergoing up to three cycles of androgen withdrawal and restoration. RESULTS. Surprisingly, clusterin deficiency did not affect the apoptotic index, and the temporal biochemical and morphological changes associated with involution and regeneration of the normal adult prostate following multiple rounds of androgen withdrawal and replacement. CONCLUSION. Clusterin is not critical for normal prostate development or androgen- regulated involution and regrowth of the mouse prostate gland, suggesting that clusterin may have distinct functions in malignant versus normal prostatic epithelial cells. Prostate 66: 1445 – 1454, 2006. # 2006 Wiley-Liss, Inc. KEY WORDS: clusterin; prostate involution; androgen; prostate regeneration INTRODUCTION Clusterin, also known as testosterone-repressed prostate message-2 (TRPM-2), dimeric acid glycopro- tein, and sulfated glycoprotein-2 (SGP-2), is a highly conserved disulfide-linked heterodimeric sulfated gly- coprotein originally isolated from ram rete testes fluid [1] and first cloned as a highly upregulated gene in involuting rat ventral prostate tissue [2]. It is present in most animal tissues and body fluids, and has been implicated in a wide variety of physiological and pathological processes including tissue remodeling, lipid transport, phagocyte recruitment, cell adhesion, reproduction, complement cytolysis, DNA repair, cell cycle regulation, and apoptotic cell death [3–5]. Clusterin has also been shown to display chaperone- like activity similar to small heat-shock proteins which are important for cytoprotection in various disease states and during periods of pathological stress [6,7]. In general, clusterin is downregulated during cell proliferation [8], but upregulated during conditions of cell stress, cell atrophy, and organ involution [3,9]. Importantly, clusterin has been reported to be upregu- lated in a number of human malignancies, including bladder, kidney, prostate, colon, breast, and lung *Correspondence to: Christopher J. Ong, The Prostate Centre at VGH, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6. E-mail: chriso@interchange.ubc.ca Received 17 March 2006; Accepted 14 April 2006 DOI 10.1002/pros.20461 Published online 24 July 2006 in Wiley InterScience (www.interscience.wiley.com). ß 2006 Wiley-Liss, Inc.