VARIATION IN RECPTOR TYROSINE KINASES AND BREAST CANCER RISKIt is clear that part of the risk of developing breast cancer is genetically determined. The genetic contributionto breast cancer risk may arise from either common or rare variants (or both) in the population. In order tosystematically assess both common and rare polymorphisms, we propose to apply a structured and highlymultidisciplinary two pronged approach designed to initially maximize the power to detect the effect of eachclass of variants on breast cancer risk. For the common variants, we will focus on cancer association studiesusing DNA from breast cancer cases and controls in the Nurses' Health Study and breast cancer cases fromthe SPORE's High Risk Cohort. The rarer missense variants will be subjected to functional cellular andmolecular assays, combined with tracking of the variants in cases of familial breast cancer. Any variant thatscores positive (for function or association) will be pursued by the complementary approach. In the previousSPORE cycle, we employed a 3-dimensional (3D) culture model of breast acini to identify genes from the'Breast Cancer 1000' cDNA library that induce phenotypic changes resembling events associated with breasttumor initiation and progression. Building on these results, we will initially focus on four candidate receptortyrosine kinases, which showed the most dramatic phenotypic effects: EGF-R, CSF-1R, ERBB2, anc IGF-1R. This research approach will be extended to other genes in future years. In this proposal, we wiltspecifically: 1) test common variants for association with breast cancer across a spectrum of risk classes, 2)test rare variants for distinguishable functional activity and association with familial and early-onset breastcancer, 3) examine the relationship between genetic variation and breast tumor receptor expression status insporadic breast cancer and 4) when possible evaluate the association of circulating ligands for thesereceptors and subsequent breast cancer risk. Using this paradigm to investigate the role of genetic variationand breast cancer, we hope to identify modestly penetrant alleles conferring breast cancer risk.
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