Matrix Metalloproteinase Gene Polymorphisms and Breast Cancer Risk and Survival

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DESCRIPTION (provided by applicant): The focused didactic training, mentorship, and research proposed in this Cancer Prevention, Control, Behavioral, and Population Sciences Career Development Award (K07) will allow the candidate to become a successful, independent investigator in cancer prevention, with a focus on genetic determinants of breast cancer risk and prognosis. In the research component, the candidate will investigate the role of matrix metalloproteinases (MMPs) in breast cancer. The human MMP family consists of over 20 proteolytic enzymes that degrade most components of the extracellular matrix and has been strongly implicated in cancer progression. Recent and growing evidence suggests that MMPs are also involved in the initial development of a tumor. Polymorphisms in certain MMP gene promoters that alter constitutive or induced expression and enzyme activity may affect individual susceptibility to disease and/or risk of disease progression. In order to further explore these relationships, the research aims of this proposal are 1) to examine the contribution of polymorphisms in MMP genes to the risk for breast cancer; 2) to determine if MMP genetic polymorphisms are associated with breast cancer type (in-situ vs. invasive) or disease stage at diagnosis; and 3) to investigate associations of MMP genetic polymorphisms with all-cause survival and breast cancer-specific survival. The proposed analyses will be based on the landmark Collaborative Breast Cancer Study, one of the largest epidemiologic studies in breast cancer. Advantages of this study include the large number of breast cancer cases and controls and the cost-effectiveness of utilizing existing resources. The didactic training in cancer biology, human genetics and genetic analysis, and molecular epidemiology proposed will fill gaps in the candidate's current training and research program. Mentors with expertise in cancer and molecular epidemiology, cell biology with a focus on MMPs, and human genetics will support the candidate throughout the award period. The didactic training and mentored research activities will provide her with opportunities to study genetic determinants of breast cancer risk and prognosis, and provide the foundation for which she can submit highly competitive grant applications in the final years of the award.