Mechanisms underlying the development of androgen-independent prostate cancer.

Prostate cancer continues to be the most common lethal malignancy diagnosed in American men and the second leading cause of male cancer mortality. The American Cancer Society estimates that during 2005, f232,090 new cases of prostate cancer will be diagnosed in the United States and 30,350 men will die of metastatic disease (1). Approximately 1 man in 5 will be diagnosed with prostate cancer during his lifetime, and 1 man in 33 will die of this disease. As the population ages, these numbers are expected to increase. Initially, almost all metastatic prostate cancers require testosterone for growth, and the role of androgen deprivation as a first-line therapy for metastatic prostate cancer has been recognized for more than 60 years (2, 3). Hormone deprivation is accomplished by surgical (orchiectomy) or medical (luteinizing hormone-releasing hormone agonists, antiandrogens) castration. Hormonal therapy leads to remissions lasting 2 to 3 years; however, virtually all patients progress to a clinically androgen-independent state resulting in death in f16 to 18 months (4–9). Androgens are primary regulators of normal prostate as well as prostate cancer cell growth and proliferation. During androgen-dependent progression, prostate cancer cells depend on the androgen receptor as the primary mediator of growth and survival (10–12). When testosterone enters the cell, it is converted by the enzyme 5a-reductase to its active metabolite, dihydrotestosterone, a more active hormone with a 5to 10fold higher affinity for the androgen receptor. Dihydrotestosterone binds androgen receptors in the cytoplasm, causing phosphorylation, dimerization, and subsequent translocation into the nucleus, thereby binding to the androgen-response elements within the DNA, with consequent activation of genes involved in cell growth and survival (10). During androgenindependent progression, prostate cancer cells develop a variety of cellular pathways to survive and flourish in an androgendepleted environment. Postulated and documented mechanisms include androgen receptor (AR) gene amplification, AR gene mutations, involvement of coregulators, ligandindependent activation of the androgen receptor, and the involvement of tumor stem cells (Fig. 1; refs. 8, 10–14). Recent Advances