Project Summary Overall goals of the proposed work: Pathological studies reveal that the development of prostate cancer is a near inevitable consequence of aging in men. It is noticed that the prostate gland is enlarged with age and the age-related re-growth of prostate epithelial cells is a critical step leading to the prostatic intraepithelial neoplasia (PIN) and prostate cancer. The proposed research will investigate how the age-related prostate growth initiates and design a novel strategy to specifically inhibit this growth process for the treatment of prostate cancer. Significance of the proposed research: Pre-malignant (PIN) lesions are characterized by intraluminal proliferation of epithelial cells and generally detected in the growing prostate in the aged men. Our studies demonstrated that the cytoplasmic WDR77 drives cellular proliferation at the early (growing) stage of prostate development and this process is re- activated to initiate growth of prostate epithelial cells in the aging prostate, which give a novel mechanism behind age-related prostate enlargement. The proposed research will identify signals that activate WDR77 to initiate cell growth and will test whether the identified compound that inhibits WDR77-driven cell growth could suppress development of prostate cancer in mouse models. Thus, the proposed research will not only provide scientific knowledge of age-related prostate enlargement but also a novel strategy for prostate cancer treatment.