TARGETING THE AP-1 TRANSCRIPTION FACTOR TO PREVENT METASTASIS FROM BREAST CANCER

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DESCRIPTION (provided by applicant): The candidate of this application is a physician scientist who obtained medical and basic biomedical research education, and completed postdoctoral research training in cancer biology. In the past ten years, the candidate has been extensively trained in cellular, molecular, and cancer biology. Immediate career goal of the candidate is to establish an independent research program to study cancer metastasis. Long-term goal is to lead independent research programs to identify targets and develop effective strategies for the prevention and treatment of cancer, and cancer metastasis. The candidate chooses to study metastasis because it counts for 90% of cancer death, while the molecular mechanisms for metastasis development are largely unknown. The elucidation of these processes may lead to the discovery of targets for effective intervention and will benefit cancer patients. The candidate is committed to a research career in cancer biology. The candidate's training and expertise in basic and clinical sciences well fit in his commitment to find a cure for cancer. The key elements of the research career plan includes a solid postdoctoral research training, a productive publication record, an important research field in cancer biology, and Baylor College of Medicine as the supporting environment that will foster candidate's career development. Breast cancer is the 2nd most common cancer in Western women, and metastasis to other organs is the major cause of death from this disease. The 5-year survival rate is approximately 98% for localized cancer, but approximately 26% for patients with distant metastasis. To date, there are no effective therapies for the prevention and treatment of metastasis from breast cancer. It is therefore an absolute clinical necessity to identify new strategies to treat established metastasis and to block the development of new metastasis. Many genes or set of genes regulate cancer metastasis. Transcription factors control the expression of these genes critical for metastasis, and thus are potential targets for intervention. The AP-1 transcription factor has been shown to regulate metastasis-related genes in breast cancer, and overexpression of a major component of AP- 1, cJun, produces a highly invasive phenotype. The candidate will test the hypothesis that the AP-1 factor is required for developing metastasis by mediating metastatic cell invasion, promoting transendothelial migration, stimulating new blood vessel formation, and regulating critical genes involved in metastasis; and blockade of AP-1 will inhibit invasion and migration of metastatic cells, prevent development of new metastasis, and suppress the growth of existing metastasis. Our objective is to define the role of AP-1 in cancer metastasis and blockade of AP-1 is an effective strategy to prevent and treat metastasis. Specifically, the candidate will (1) determine whether AP-1 is required for invasion and metastasis using xenograft and transgenic mouse models; (2) investigate whether AP-1 promotes transendothelial migration, new blood vessel formation; and (3) define the molecular mechanisms how AP-1 regulates migration and invasion by mediating E-cadherin, a major AP-1-regulated gene involved in metastasis. The proposed studies will determine whether the AP-1 factor is a major regulator of metastasis and provide the foundation and rationale to develop agents capable of disrupting the metastatic process. PUBLIC HEALTH RELEVANCE: We hypothesized that the AP-1 factor is required for developing metastasis by mediating metastatic cell invasion, promoting transendothelial migration, stimulating new blood vessel formation, and regulating critical gene expression involved in metastasis. The proposed studies will determine whether the AP-1 factor is a major regulator of metastasis. Results from this project will provide the foundation and rationale to develop agents capable of disrupting the metastatic process.