Cancer of the prostate gland is one of the most common invasive malignancies in males in the United States. Prostate cancer is generally detected in aged men and because of increasing life expectancy and better diagnosis of the disease, its rate of incidence is expected to increase. It is estimated that 218,890 new prostate cancer cases will be diagnosed in the United States alone in the year 2007, and approximately 27,050 prostate cancer-related deaths are predicted during this year alone in the U.S. When the prostate cancer cells achieve androgen-independence, in particular at advanced stages of disease, they offer resistance to conventional therapies. The prostate cancer cells arising from such tumors are highly invasive, resistant to radiation and chemotherapeutic agents, and possess capability of renewing themselves. Such tumor cells exhibit high rate of proliferation and even metastasize and invade to distant parts of body. About 15% of prostate cancer patients generally show biochemical progression after radical prostatectomy due to persistence of isolated tumor cells.

Despite recent improvements in diagnostic and therapeutic techniques post-treatment, local and distant recurrence and resistance to conventional therapies are still the major problems in the management of prostate cancer. Metastatic spread of prostate cancer to distant sites is the major cause of prostate cancer-related deaths in humans. Thus, for the development of effective therapies for advanced disease, it is essential to understand the proliferative and invasive behavior of prostate cancer cells. The lack of effective therapies for advanced prostate cancer reflects, to a large extent, the paucity of knowledge about the molecular pathways involved in the pathogenesis of prostate cancer and biomarkers to access disease development, impact of treatment, and effect of preventive intervention. Thus, the identification of new predictive biomarkers, especially those that are indicative of proliferation and invasiveness, will be important for improving clinical management, outcome, and survival of prostate cancer patients. These biomarkers will also be excellent candidate targets for staging the disease and establishing effectiveness of therapeutic and chemopreventive intervention of patients with prostate cancer. In our exciting preliminary studies, we observed that Bmi-1 protein is secreted by prostate epithelial cells and its levels are elevated in prostate cancer patients. In recent years, Polycomb group of proteins, of which Bmi-1 protein is a member, have received significant attention because of their role in various types of malignancies. Our global hypothesis is that Bmi-1 promotes proliferation and invasiveness of prostate cancer in humans through its interaction with Sonic hedgehog and Wnt/beta-catenin signaling pathways, which are reported to be highly active during the development and progression of human prostate cancer.

In this proposal, we want to test our hypothesis that the reduction in the level of Bmi-1 protein by novel molecular and therapeutic approaches will reduce the progression and invasiveness of prostate cancer. The plan presented here will establish the role of Bmi-1 in the invasion and development of tumors arising from prostate cancer cells. This work also will provide an understanding for the role of Bmi-1 as a potential prognostic and diagnostic biomarker of prostate cancer. Our plan presented here will lay the foundation for future in-depth studies to establish Bmi-1 as a suitable target to monitor the therapeutic response during prostate cancer treatment protocols.