) Project C: Oral Contraceptives, Hormonal Risk Factors, and BRCA1. Mutations in the breast cancer susceptibility gene BRCA1 may be involved in a substantial number of breast cancers diagnosed at an early age. However, the age at which breast cancer occurs appears to vary substantially, even in women from the same family with the same mutation. This suggests that other, genetic or non-genetic, factors play a role in whether or when breast cancer occurs in women with a BRCA1 mutation. Epidemiological evidence suggests that oral contraceptive (OC) use at an early age may increase risk of breast cancer. Further, OC use may be particularly detrimental in women with a family history. A number of environmental risk factors other than exogenous hormone use probably also work through a hormonal mechanism; these include age at first birth, parity, possibly abortion, and physical exercise. All these factors can be manipulated, and therefore have implications for prevention. These """"""""hormonal"""""""" risk factors appear to have different, if not opposite, effects in women with a family history than in women with no such history. The reason for this is unknown. However, BRCA1 expression appears to be regulated by hormones in experimental studies. Further, women with a family history are more likely to have a BRCA1 mutation. It is therefore possible that the apparent effect modification by family history is caused by BRCA1 status. We propose to conduct a population-based study that investigates whether the presence of specific BRCA1 mutations modify 1) the effects of oral contraceptive use, 2) the effects of """"""""hormonal"""""""" risk factors such as age at first birth, number of pregnancies, and number of abortions, and 3) the protective effect of physical exercise, on breast cancer risk. In addition, this study will provide information as to the frequency of these mutations in younger breast cancer patients, and we will explore the associations between BRCA1 status and other breast cancer risk factors such as mammographic densities. This study will provide valuable epidemiologic information regarding the role of BRCA1 in breast cancer etiology, and could yield important results in developing intervention regimens and appropriate counseling for women with a BRCA1 mutation.
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