Prevention of Prostate Carcinogenesis in Transgenic Mice
Principal Investigator: Fischer, Susan M
Institution: University of Texas MD Anderson Cancer Center
NCI/DCP Program Director: Kim, Young S
Project ID (Grant #): 1R01CA107588-01
RFA/PA Number: RFA-CA-04-004
Project Funding Period: 6/1/2004 to 5/31/2009
Description (provided by applicant)
Prostate cancer is the most commonly diagnosed cancer in men in the USA. However, the rates of clinically significant prostate tumors are considerably lower in Asian countries than in the USA and other Western countries. An increase in risk of developing prostate cancer is observed in males emigrating from countries with low prostate cancer rates to countries where the rate is high, suggesting that dietary factors may underlie the East-West differences. Differences in dietary patterns with regard to consumption of fruits, vegetables and soy-based products, whole grains, and type and quantity of dietary fat have been implicated. A number of potential chemopreventive agents for prostate cancer have been identified based on epidemiological correlations or their activity in cell lines. Recent data suggest that both the cyclooxygenase-2 (COX-2) and the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathways are upregulated in prostate cancers. In this application, we will evaluate a number of dietary components and fats that have been shown to block cancer cell proliferation for their ability to block either the COX-2 or the P13 K/Akt pathways as their primary mechanism of action. Because insulin-like growth factor- 1(IGF-1) is believed to play a role in human prostate cancer development, these agents will be evaluated for their ability to inhibit prostate carcinogenesis in an IGF-1 transgenic mouse model (BK5.IGF-1 mice) of spontaneous prostate cancer. We will test the hypothesis that dietary components having either strong inhibitory effects on COX-2 expression or activity and/or on PI3K/Akt activity will have significant chemopreventive activity for prostate cancer and that this effect will be potentiated by altering the type of dietary fatty acids consumed. The Specific Aims are to (1) evaluate the ability of a series of agents previously demonstrated to inhibit cancer cell proliferation for their ability to inhibit either COX-2 expression or activity, or PI3K/Akt activity (kinase activity/phosphorylation state); (2) evaluate the ability of specific types of dietary fats to alter prostaglandin (PG) levels as well as COX-2 expression levels and Akt activity in BK5.IGF-1 prostates in vivo; and (3) examine (i) the most effective dietary components that inhibit either the COX-2 pathway and/or the PI3K/Akt pathway (Aim 1) for their ability to inhibit spontaneous prostate carcinogenesis in vivo and (ii) the ability of specific dietary fatty acids (Aim 2) to enhance or inhibit the development of spontaneous prostate cancer in the BK5.IGF-1 model.
