Estrogen Metabolites, Related Genes and Breast Cancer

描述（由申请人提供）：纽约大学妇女健康研究（NYUWHS）队列在阐明雌激素和雄激素与乳腺癌的关系方面发挥了主导作用，该研究基于1985-91年间从14,000多名35-65岁健康女性中前瞻性获得的血液样本。我们现在与来自于默奥的瑞典北部健康与疾病研究的另一个队列合作，来解决雌激素代谢物在乳腺癌中的作用问题。拟议的拨款期限将把纽约大学卫生研究所的随访时间延长至平均约19年，并将允许累计近1000例乳腺癌病例，而于默奥研究将有600多例病例。两项研究的随访率和癌症病例确诊率都很高。这项研究将调查雌激素代谢物的水平——可能是雌激素性的，也可能是遗传毒性的——对乳腺癌风险的影响程度，以及雌激素代谢基因的功能多态性在多大程度上预测雌激素代谢物水平和乳腺癌风险。我们假设：16 α -羟孕酮的循环水平与乳腺癌风险呈正相关，2-羟孕酮与16 α -羟孕酮的比例与乳腺癌风险呈负相关；与16 α -羟基化（CYP3A4和CYP3A5）和4-羟基化（CYP1B1）酶活性改变相关的遗传多态性与乳腺癌风险相关。巯基转移酶和葡萄糖醛酸酶基因的功能多态性会降低雌激素结合活性，这与乳腺癌风险增加有关。在过去的五年中，NYUWHS队列已经成为一系列合作者调查各种癌症（乳腺癌，结肠直肠癌，子宫内膜癌，卵巢癌）的众多危险因素的基础，例如，IGF-I及其结合蛋白；有机氯;血清类胡萝卜素、植物雌激素、叶酸和同型半胱氨酸；黄体生成素和DNA修复基因的多态性。前瞻性收集的血清样本、DNA、生活方式和饮食数据的可用性，加上延长的随访和癌症数量的增加，将使这项研究能够继续促进对一系列癌症的各种生物学风险因素的调查。

DESCRIPTION (provided by applicant): The NYU Women's Health Study (NYUWHS) cohort has played a leading role in elucidating the associations of estrogens and androgens with breast cancer, based on blood samples that were obtained prospectively in 1985-91 from over 14,000 healthy women of ages 35-65. We now team up with another cohort from the Northern Sweden Health and Disease Study in Umea to address questions about the roles of estrogen metabolites in breast cancer. The proposed grant period would extend the NYUWHS follow-up to about 19 years on average and would permit the accrual of nearly 1,000 incident breast cancer cases, while the Umea study will have over 600 cases. The follow-up and cancer case ascertainment rates have been high in both studies. The study will investigate how much levels of estrogen metabolites - which can be both estrogenic and genotoxic - affect breast cancer risk, and the degree to which functional polymorphisms in estrogen metabolism genes are predictive of estrogen metabolite levels and of breast cancer risk. We hypothesize that: Circulating levels of 16alpha-hydroxyestrone are positively associated with breast cancer risk, and the 2-hydroxyestrone to 16alpha-hydroxyestrone ratio is negatively associated with breast cancer; Genetic polymorphisms associated with altered activity of enzymes catalyzing 16alpha-hydroxylation (CYP3A4 and CYP3A5) and 4-hydroxylation (CYP1B1) are associated with breast cancer risk. Functional polymorphisms in the sulfotransferase and glucuronidase genes that diminish estrogen conjugation activity are associated with increased breast cancer risk. Over the last five years, the NYUWHS cohort has been the basis for investigations, with a series of collaborators, of numerous risk factors for various cancers (breast, colorectal, endometrial, ovarian) e.g., IGF-I and its binding proteins; organochlorines; serum carotenoids, phytoestrogens, folate and homocysteine; polymorphisms in luteinizing hormone and DNA repair genes. The availability of serum specimens, DNA, and lifestyle and dietary data collected prospectively, combined with the extended followup and increasing numbers of cancers, will allow the study to continue to foster the investigation of various biological risk factors for a range of cancers.