Causes and mechanisms involved in the development of most cancers are not well known. As for breast and endometrial cancers, most risk cancers indicate that sex hormones are important. However, hormone-related factors-like nulliparity, late age at first birth, early menarche, late menopause, long-term use of oral contraceptives or hormone replacement therapy-together with first-degree family history, explain only half of all breast cancers occurring. Further, in the presence of a high-risk factor, the added absolute risk is usually small. For instance, hormone replacement therapy (HRT) for many years confers an attributable risk increase of only about one percent. It is likely that some individuals are at higher susceptibility of hormonal carcinogenesis. Interest is now focusing on inherited variations in life-time exposures to estrogens in target organs. The proposed study aims to explore the hypothesis that functional polymorphisms of the gene for the CYP1B1 and COMT enzymes entail different activity levels, for metabolic activation of estradiol to reactive catechol estrogens, and for clearance of such genotoxic compounds, respectively. Specifically, a high-activity allele of the CYP1B1 gene may increase the risk of breast endometrial cancer by increasing the load of genotoxic metabolites, or conversely a low-activity allele may enhance the risk through higher levels of estradiol that increase proliferation; the lowest activity allele of COMT is the most adverse through a low capacity to clear genotoxic metabolites. The study will be conducted among subjects who participated in two coordinated population-based case-controls studies, in which information on risk factors for breast and endometrial cancer was collected through questionnaires. From these two parent studies, 1200 breast cancer cases (out of 3900), all 800 endometrial cancer cases, phenotypically well characterized-and 1300 coordinated control subjects (out of 4200) are being enrolled in molecular epidemiological studies. These concern associations between selected ER, VDR, and AR gene polymorphisms and the risk of cancer in the breast and endometrium. The same data base will be used for the proposed study. After informed consent, the majority of the women (75%) donate blood and an small proportion of the case subjects (5%) allow use of archived specimens (also for deceased cases) for production of DNA. In this study, DNA will be genotyped for high and low activity alleles of the CYP1B1 gene, recently shown to be functionally polymorphic, and for three different activity alleles of the COMT gene. These alleles will be analyzed, with the highest statistical power hitherto, as risk factors singly, jointly and in subgroups of women with respect to risk factors. This research is innovative by examining for the first time how variants of genes for enzymes involved in estrogen metabolism affect the risk for two of the most important hormone-related cancers in women. It gives prospects for better definition of individual susceptibility and thereby a possibility for selective advice and improved cancer prevention.