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相关性方面发挥了主导作用，该研究基于1985-91年从14，000多名35-65岁的健康妇女中前瞻性获得的血液样本。我们现在与另一个来自瑞典北方健康与疾病研究的队列研究团队合作，以解决有关雌激素代谢物在乳腺癌中的作用的问题。拟议的赠款期限将把纽约大学世界卫生大学的随访时间平均延长到19年左右，并将允许增加近1,000例乳腺癌病例，而Umea研究将有600多例病例。在这两项研究中，随访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-这可能是雌激素和遗传毒性-影响乳腺癌的风险，以及雌激素代谢基因的功能多态性预测雌激素代谢物水平和乳腺癌风险的程度。我们假设：16 α-羟基雌酮的循环水平与乳腺癌风险呈正相关，2-羟基雌酮与16 α-羟基雌酮的比例与乳腺癌呈负相关;与催化16 α-羟基化（CYP 3A 4和CYP 3A 5）和4-羟基化（CYP 1B 1）的酶活性改变相关的遗传多态性与乳腺癌风险相关。降低雌激素结合活性的磺基转移酶和葡萄糖醛酸酶基因的功能多态性与乳腺癌风险增加有关。在过去的五年里，纽约大学妇女卫生研究所的队列一直是研究的基础，与一系列合作者一起，研究了各种癌症（乳腺癌、结肠直肠癌、子宫内膜癌、卵巢癌）的许多风险因素，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修复基因多态性。前瞻性收集的血清标本、DNA、生活方式和饮食数据的可用性，加上长期随访和癌症数量的增加，将使该研究能够继续促进对一系列癌症的各种生物风险因素的研究。

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.