The Role of Androgens on Breast Cancer Susceptibility across the Lifecourse.

项目总结/摘要 尽管对雌激素在乳腺癌风险中的作用进行了广泛的研究，但对雌激素在乳腺癌风险中的作用知之甚少。 雄激素是雌激素的重要前体，在改变乳腺癌易感性方面具有重要作用。此外，还有一个 迫切需要进行病因学调查的作用，雄激素在妇女和青春期女孩谁是在 患乳腺癌的风险更高，从他们的乳腺癌家族史。拟议项目将解决这一问题 通过使用纵向数据的培训和研究综合方案， 以家庭为基础的队列研究动态雄激素模式对乳腺癌风险的影响， 生命历程乳腺癌风险模型中的生殖风险因素（例如，初潮年龄，头胎年龄， 产次）是雌激素暴露的代表，但这些因素不完全捕获激素环境， 特别是雄激素水平，它在青春期之前上升，并受到包括压力在内的其他过程的影响。 使用单雄激素或多雄激素受体拮抗剂的血清浓度， 雌激素这项提案将调查完整的类固醇激素代谢组，包括雄激素， 雌激素、孕激素和糖皮质激素代谢物与乳腺癌风险的关系。测量 雄激素水平，而不是雌激素，在月经周期中变化更大， 青少年和绝经前妇女，因此可能在临床风险评估中更有用。 通过使用现有的生物标本进行家庭队列，我们将调查是否的幅度 雄激素和乳腺癌风险之间的关联以及雄激素和中等风险因素之间的关联 （青春期和月经周期特征）在高、中、低潜在性 遗传易感性是准确风险评估的关键问题。具体来说，我们将分析来自 两项纵向研究丰富了有乳腺癌家族史的女孩和妇女， 潜在的癌症遗传易感性。第一项是对女性进行的前瞻性巢式病例对照研究 参与前瞻性家族研究队列（n=75例病例，150例对照，来自2，136例队列 不受影响的女性）。第二项是LEGACY女孩研究，这是一项多中心队列研究，招募了1040名6- 10岁的女孩。 基线为13年，过去六年每半年跟踪一次。这些队列的分析将 包括三个关键时期--成年期、青少年期和儿童期--以解决具体假设， 尿雄激素代谢产物和乳腺癌，青春期，体型和早期生活压力。我们将使用 移动的健康方法来跟踪月经周期在真实的时间，以更好地表征激素模式。的 建议的研究将通过1）以家庭为基础的研究设计的经验和教学培训来补充 和风险评估，2）基于机械和自动化的分析，3）传播和实施 科学这项研究和培训将启动一项关于遗传和基因的独立研究计划， 生物文化因素影响女孩和妇女的激素轨迹和乳腺癌风险。

Project Summary/Abstract Despite extensive research on the role of estrogens in breast cancer risk, little is known about the role of androgens, an important precursor to estrogen, in altering breast cancer susceptibility. Further, there is a critical need for etiologic investigation of the role of androgens in women and adolescent girls who are at higher risk of breast cancer from their family history of breast cancer. The proposed project will address this major gap in scientific evidence through an integrated program of training and research using longitudinal family-based cohorts to investigate the effect of dynamic androgen patterns on breast cancer risk across the lifecourse. Reproductive risk factors in breast cancer risk models (e.g., age at menarche, age at first birth, parity) are proxies for estrogen exposure, but such factors incompletely capture the hormonal environment, particularly androgen levels, which rise prior to puberty and are affected by other processes including stress. Some improvement in risk assessment has been seen using serum concentrations of single androgenic or estrogenic hormones. This proposal will investigate the full steroid hormone metabolome, including androgen, estrogen, progestagen and glucocorticoid metabolites, in relation to breast cancer risk. Measurement of androgens levels, as opposed to estrogens that vary more across the menstrual cycle, is more feasible in adolescents and pre-menopausal women and thus likely will be more useful in clinical risk assessment. Through use of ongoing family cohorts with existing biospecimens, we will investigate whether the magnitude of the associations between androgens and breast cancer risk and androgens and intermediate risk factors (puberty and menstrual cycle characteristics) differ in populations with high, intermediate and low underlying genetic susceptibility, a critical question for accurate risk assessment. Specifically, we will analyze data from two longitudinal studies enriched with girls and women with a family history of breast cancer, which represents underlying genetic susceptibility to cancer. The first is a prospective nested case-control study of women participating in the Prospective Family Study Cohort (n=75 cases, 150 controls from a cohort of 2,136 unaffected women). The second is the LEGACY Girls study, a multi-site cohort that enrolled 1040 girls ages 6- 13 years at baseline and has followed them semi-annually for the past six years. Analyses in these cohorts will include three key periods—adulthood, adolescence and childhood—to address specific hypotheses focusing on urinary androgen metabolites and breast cancer, puberty, body size, and early-life stress. We will use mobile health methods to track menstrual cycles in real time to better characterize hormone patterns. The proposed research will be complemented by experiential and didactic training in 1) family-based study design and risk assessment, 2) mechanistic- and trajectory-based analytics, 3) dissemination and implementation science. This research and training will launch a program of independent research on the genetic and biocultural factors shaping girls and women's hormone trajectories and breast cancer risk.