Matrix Metalloproteinase Gene Polymorphisms and Breast Cancer Risk and Survival

描述（由申请人提供）：本次癌症预防、控制、行为和人口科学职业发展奖（K07）中提出的重点教学培训、指导和研究将使候选人成为癌症预防领域成功的独立研究者，重点研究乳腺癌风险和预后的遗传决定因素。在研究部分，候选人将研究基质金属蛋白酶（MMPs）在乳腺癌中的作用。人类MMP家族由20多种蛋白水解酶组成，可降解细胞外基质的大部分成分，并与癌症进展密切相关。最近越来越多的证据表明MMPs也参与了肿瘤的初始发展。某些MMP基因启动子的多态性改变了组成或诱导表达和酶活性，可能影响个体对疾病的易感性和/或疾病进展的风险。为了进一步探索这些关系，本提案的研究目的是：1)检查MMP基因多态性对乳腺癌风险的贡献；2)确定MMP基因多态性是否与乳腺癌类型（原位与侵袭性）或诊断时的疾病阶段相关；3)研究MMP基因多态性与全因生存和乳腺癌特异性生存的关系。拟议的分析将基于具有里程碑意义的乳腺癌合作研究，这是乳腺癌领域最大的流行病学研究之一。这项研究的优势包括大量的乳腺癌病例和对照，以及利用现有资源的成本效益。在癌症生物学、人类遗传学和遗传分析以及分子流行病学方面的教学培训将填补候选人目前培训和研究计划的空白。在整个奖励期间，具有癌症和分子流行病学、以MMPs为重点的细胞生物学和人类遗传学专业知识的导师将支持候选人。教学培训和指导研究活动将为她提供研究乳腺癌风险和预后的遗传决定因素的机会，并为她在该奖项的最后几年提交极具竞争力的资助申请奠定基础。

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.