Lifetime body weight and premenopausal breast cancer

描述（由申请人提供）：出生体重和一生中不同阶段的体重被认为会影响绝经前乳腺癌的风险。高出生体重与绝经前乳腺癌的风险增加有关。更奇怪的是，儿童和成年早期的超重和肥胖一直与绝经前乳腺癌的风险降低有关。这些关联背后的机制尚未阐明。体重和身体质量在生命的不同阶段对乳腺癌风险的影响是如何相互关联的还没有得到充分的研究。出生体重与儿童和青少年早期体重与绝经前乳腺癌风险的相反方向的关系令人困惑。然而，评估一生中与这些人体测量因素相关的乳腺癌风险是复杂的，因为不仅出生体重、童年体重、青春期和成年早期的体重可能相关，这些人体测量因素还可能影响其他变量，如初潮年龄、身高，这些变量可能与后来的体重和乳腺癌风险有关。此外，一生中人体测量因素与绝经前乳腺癌风险之间关联的生物学途径尚不清楚。在动物实验中，瘦素受体有缺陷的肥胖啮齿动物没有发生乳腺肿瘤。我们建议在护士健康研究II （NHS II）中，通过1989年至2005年的两年一次的随访，调查绝经前乳腺癌风险与出生体重、5岁和10岁时的相对体重、18岁时的体重指数（BMI）和成年早期更新的BMI之间的关系。我们进一步建议以巢式病例对照的方式评估瘦素血浆水平和瘦素基因和瘦素受体基因的遗传多态性。我们建议研究在乳房x光检查中检测到的乳腺密度是否可能是体重与绝经前乳腺癌之间关联的一个时间依赖性混杂因素或效应调节因子。这将是第一个将体重与乳腺癌发病率联系起来的终身研究。它还非常高效，因为它借鉴了已经为NHS II收集的问卷数据、血液样本和乳房x光片。

DESCRIPTION (provided by applicant): Birth weight and body weight at various points during lifetime have being suggested to influence the risk of premenopausal breast cancer. A high birth weight has been associated with an increased risk of premenopausal breast cancer. More curiously, overweight and obesity during childhood and early adulthood have consistently been linked to a decreased risk of premenopausal breast cancer. The mechanisms underlying these associations have not been elucidated. How body weight and body mass at different stages in life may interrelate in their impact on breast cancer risk has not been sufficiently explored. The opposite direction of the association of birth weight on one hand and of childhood and early adolescent body mass on the other hand with premenopausal breast cancer risk is perplexing. However, evaluating breast cancer risk in relation to these anthropometric factors during lifetime is complicated because not only may birth weight, childhood weight, and body mass during adolescence and early adulthood be related, these anthropometric factors can also influence other variables, such as age at menarche, height, which may be related to both later body mass and the risk of breast cancer. Furthermore, biological pathways underlying the association between anthropometric factors during lifetime and premenopausal breast cancer risk are not well understood. In animal experiments, obese rodents with a defect in the leptin receptor did not develop mammary tumors. We propose to investigate premenopausal breast cancer risk in relation to birth weight, relative weight at age 5 and 10, body mass index (BMI) at age 18 and updated BMI in early adulthood through biannual follow-up from 1989 through 2005 in the Nurses' Health Study II (NHS II). We further propose to evaluate leptin plasma levels and genetic polymorphisms of the leptin gene and the leptin receptor gene in a nested case-control fashion. We propose to examine whether breast density as detected in a mammogram may be an time-dependent confounder or an effect modifier of the association between body mass and premenopausal breast cancer. This will be the first study taking a life-course approach in linking body mass with breast cancer incidence. It is also highly efficient since it borrows from questionnaire data, blood samples, and mammograms already collected for the NHS II.