The long-term objectives of this project are to characterize the interaction between dietary isoflavone and MDM2 oncogene, to evaluate the potential of MDM2 as novel targets for cancer chemoprevention, and to translate these findings into more rational approach to prevention of human cancers. Genistein is a dietary isoflavone known to have chemopreventive effects in several human cancer models, including those of the breasts and prostate. However, the mechanisms for its cancer preventive and growth inhibitory effects are not fully understood. The MDM2 oncoprotein has p53-dependent and -independent tumorigenic activities in various types of human cancers including prostate and breast cancers. It also has been suggested as a novel target for cancer prevention and treatment. This proposal is based on our preliminary data that support a previously unrecognized mechanism of action for genistein: direct down-regulation of the MDM2 oncogene. We have demonstrated that, in a dose-dependent manner, genistein inhibits MDM2 expression in human cancer cells (and normal cells), and that the inhibitory effects occur at both transcriptional and post-translational levels, and that the inhibitory effects occur in vivo and are related to genitein's anti-tumor effects. This proposal is designed to test the central hypothesis that inhibition of MDM2 is the major mechanism by which genistein exerts its anti-cancer effects. Three hypothesis-driven specific aims are proposed: 1). to establish that genistein specifically inhibits MDM2 and that this inhibition is the primary mechanism by which the compound exerts its anti-cancer effects.; 2). to evaluate the in vivo effects of genistein on MDM2 with respect to its cancer preventive effects; and 3). to determine the mechanisms by which genistein regulates MDM2. Successful completion of the specific aims will provide a basis for further investigation of MDM2 as a target for cancer prevention and treatment and will generate knowledge with respect to mechanisms of action for genistein (and maybe other dietary isoflavones)-based cancer control approaches. There also is considerable potential of exploiting MDM2-associated pathways for human cancer prevention and therapy. ? ? ?
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