Experimental and clinical evidence suggests that endogenous sex hormones and insulin-like growth factor 1 (IGF-I) may contribute to the etiology of breast cancer. We propose to examine whether most known polymorphisms of a number of genes involved in the biosynthesis and catabolism of estrogens (CYP11a, CYP17, EDH17beta2, CYP1A1, CYP1A2, CYP1B1, COMT), and those for the androgen receptor, estrogen receptor and IGF-I genes are related to the risk of breast cancer and proliferative breast disease. Also, we plan to study whether these polymorphisms and plasma levels of IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) are related to degree of cell proliferation in non-cancerous tissues from women with fibrocystic disease. We propose to conduct a case-control study nested within an ongoing randomized Breast Self Examination Trial being conducted in Shanghai, China, involving 285,628 women. We will analyze blood specimens that will have been collected and received in Seattle by the end of year 2000 for a study of diet, cell proliferation, and breast cancer in Shanghai (R01 CA75332) from approximately 542 women with breast cancer, 627 women with fibrocystic disease, and 793 age-matched controls. Demographic variables, reproductive history, and (for cases) extent of cell proliferation of non-cancerous breast tissue based on morphological classification will be available from the dietary study. We will test the hypotheses that 1) the risk of breast cancer and proliferative breast disease are related to one or more alleles that are believed to correspond to a high level of estradiol, testosterone or IGF-I (adjusted for IGFBP-3), or high activities of androgen receptors and estrogen receptors; 2) the mechanism by which some of the risk alleles exert their influence is through the promotion of cell proliferation; and 3) the effect of some of the risk alleles may be modified by reproductive and other factors associated with breast cancer. Because of the size and scope of the study, we believe it has the potential to substantially advance our understanding of the etiology of breast cancer. Our ultimate goal is to provide information to identify women at high risk of breast cancer, and to aid in the formulation of prevention strategies for these women.
