Abstract: Prostate cancer is the most commonly diagnosed cancer in men and affects millions of people. In recent years both the detection and incidence have increased dramatically. The natural history of prostate cancer is enigmatic leading to significant controversies concerning screening tests and proper therapeutic management. The only established systemic therapy for this disease focuses on androgen ablation. Androgen deprivation induces programmed cell death in hormone-dependent prostatic cancer. However, androgen-independent cells are present early in the evolution of prostate cancer and virtually all patients eventually develop androgen-independent tumor, a serious clinical problem for which no effective therapy exists. The mechanisms of development and biochemical pathways that contribute to androgen-independent growth are unknown. Existing classifications of prostate cancer offer little information regarding prognosis or predicted response to therapy for individual patients. Molecular profiles that distinguish androgen-dependent from androgen-independent prostate cancer will provide insight into the critical pathways that regulate tumor growth and response to therapy, and can be used for classification with regard to hormone sensitivity. The overall goal of our research program is to characterize the molecular events underlying the clinical features of prostate cancer and provide a basis for molecular classification and targeted therapy. Comprehensive analyses of a human prostate cancer xenograft have demonstrated that expression levels in large numbers of genes change dramatically in the course of selection for androgen-independent growth. Androgen-independent tumors have a distinct molecular profile resulting from altered expression of many genes, some of which are known to play a role in the androgen signal transduction pathway, but many are of unknown function. Based on this encouraging result we expect that androgen-independent primary human prostate cancer will have a distinct molecular profile. We propose 1) to define molecular profiles that are representative of androgen-independent prostate carcinoma by comprehensive, microarray-based gene expression analysis and comparison of androgen-dependent and androgen independent tumors, 2) to develop robust molecular histopathologic methods to identify and quantitate androgen-dependent and -independent tumor cell subclones within primary human prostate carcinomas for molecular classification of individual tumors, and 3) to analyze the relationship between molecular classification and clinical course of disease in statistically sound retrospective and prospective studies. These studies will provide the basis for an in-depth understanding of the role of androgens in prostate cancer, mechanisms for development of hormone refractory disease and the clinical utility of a molecular classification based on this information.