The CTBR awarded 1 pilot project for our 2014-2016 grant year. The pilot project receives $70,000/year for two years.
MDM2 Oncogenic Functions Promoting Metastasis and Circulating Tumor Cells
PI: Jill Bargonetti, Biology Department
MDM2 proteins are growth-promoting molecules that interact with wild-type p53 and oncogenic mutant p53, as well as with multiple factors involved in ribosome biogenesis, DNA repair, and cancer cell metastasis. Our lab has made significant contributions to the understanding of the biological pathways regulated by MDM2 oncogenic isoforms, many of which are not dependent on the degradation of p53This grant application explores the participation, and molecular mechanisms of action, of oncogenic MDM2 proteins in promoting cancer cell metastasis from the early stage of solid tumors towards the shedding of cancer cells into blood circulation. Tumor cells shed into the blood are called circulating tumor cells (CTCs). CTCs are known to be detectable even in early stages of cancer and their numbers correlate with prognosis. The Ogunwobi laboratory has made significant contributions towards the understanding of CTC biology using mouse models that implicate COX-2 pathways. This collaborative pilot proposal contains two aims that explore the influence of MDM2 on breast cancer metastasis in the presence of wild-type and mutant p53 in estrogen receptor positive breast cancer. We will use our well-documented short hairpin mdm2 knockdown breast cancer model in MCF-7 cells (with wild-type p53) and T47D cells (with mutant p53). Aim 1: Determine, for the first time in a mouse model, the ability of MDM2 expression in human breast cancer cells to promote metastasis and CTCs. Aim 2: Test the hypothesis that human MDM2 promotes breast cancer cell invasion and metastasis by activation of NFkB and the up-regulation of COX-2. Studies on MDM2 in invasion and CTC promotion through activation of the NFkB pathway are novel and should break new ground. The coordinated use of a biological mouse model and in vitro molecular pathway experiments will elucidate the functional relevance and molecular targets of breast cancer-associated MDM2. The finding that MDM2 provokes the formation of CTCs and increased COX-2 through NFkB would position MDM2 as an instrumental biomarker for breast cancer metastasis.