Maternal obesity, intrauterine gene expression and breast cancer

描述(由申请人提供)：越来越多的证据表明子宫内环境对乳腺癌发生的重要性。母亲超重和肥胖可能是乳腺癌风险的最重要的围产期预测因素之一。许多研究表明，高出生体重与高产妇体重指数(BMI)有关，与绝经前妇女患乳腺癌的风险增加有关。胰岛素样生长因子(IGF)-II在胚胎和胎儿的发育和生长中起着重要作用。IGF2是一个仅由父亲的等位基因表达的印记基因。由于DNA低甲基化导致IGF2在重编程过程中的印迹丢失(LOI)，导致双等位基因表达，通过促进细胞增殖和减少凋亡，导致IGF-II产量增加和胎儿生长。IGF2的LOI与乳腺癌的发生发展有关。在乳腺组织、正常组织和乳腺癌患者的淋巴细胞中发现了IGF2的双等位基因表达。肥胖和糖尿病的宫内环境导致高出生体重和脐带血中高水平的胰岛素和瘦素。瘦素代谢可能在子宫中被编程，并决定整个生命过程中循环中的瘦素水平。高瘦素水平与患乳腺癌的风险增加有关。我们将使用我们科室分娩现场的脐带血样本来研究母亲超重和肥胖在IGF2的LOI中的作用。利用护士健康研究II中关于出生体重、癌症诊断前采集的血液样本以及护士中确诊的绝经前乳腺癌病例的数据，我们将探讨瘦素的中介作用。我们建议检验以下假设：1)母亲高BMI与女儿IGF-2的LOI显著增加相关，2)高出生体重与绝经前乳腺癌发病率增加之间的关联部分通过瘦素血浆水平来调节。

DESCRIPTION (provided by applicant): A growing line of evidence suggests the importance of the intrauterine environment for mammary carcinogenesis. Maternal overweight and obesity are likely among the most important perinatal predictors of breast cancer risk. Numerous studies have associated high birthweight, which is linked to high maternal body mass index (BMI), with an increased risk of breast cancer among premenopausal women. Insulin-like growth factor (IGF)-II plays a major role in embryonic and fetal development and growth. IGF2 is an imprinted gene expressed only by the paternal allele. Loss of imprinting (LOI) of IGF2 during reprogramming due to DNA hypomethylation leads to biallelic expression, resulting in increased IGF-II production and extreme fetal growth through increased cell proliferation and reduced apoptosis.The LOI of IGF2 has been associated with the development and growth of breast cancer. Biallelic IGF2 expression has been found in breast tissue and in normal tissue and lymphocytes from breast cancer patients. The obese and diabetic intrauterine environment fosters a high birthweight and high cord blood levels of insulin and leptin. Leptin metabolism may be programmed in utero and determine circulating leptin levels throughout the life course. High leptin levels have been associated with an increased risk of breast cancer.Using cord blood samples from the labor floor in our department we will examine the role of maternal overweight and obesity in LOI of IGF2. Using data from the Nurses' Health Study II on birthweight, blood samples obtained prior to diagnosis of cancer, and confirmed cases of premenopausal breast cancer among the nurses, we will explore the mediating role of leptin. We propose to test the following hypotheses: 1) a high maternal BMI is associated with a significantly increased LOI of IGF-2 in the daughter, and 2) The association between a high birthweight and an increased incidence of premenopausal breast cancer is partially mediated through leptin plasma levels.