Early Risk Factor Related Epigenetic Alterations in Breast Cancer Pathogenesis

几个公认的风险因素，如年龄、产次、家族史和体重指数(BML)，都会导致 浸润性乳腺癌是女性中最常见的非角质形成细胞癌 美国。目前的乳腺癌模型显示从正常乳腺向良性乳腺进展。 病变，非侵袭性疾病，然后是侵袭性肿瘤。已确诊的乳腺癌之间的关系 乳腺肿瘤的危险因素和表观遗传学特征已开始被描述，表观遗传学 已知包括DNA甲基化改变在内的改变是乳腺癌发生的早期因素。 然而，在浸润性乳腺癌中发生的表观遗传学改变的存在是 在正常乳腺、癌前病变和非侵袭性乳腺的连续体中未被充分探索 癌症。我们公布的初步数据表明，乳腺癌DNA与显著的独立相关性 甲基化与可改变的乳腺癌危险因素的关系。在这里，我们建议检验以下假设 正常乳腺、癌前病变和非浸润性癌症中的DNA甲基化变异相关 有疾病风险因素并进展为侵袭性疾病。这项工作将利用现有的组织和 来自登记在新汉普郡乳房摄影网络的女性的患者数据资源，允许 良性病变和侵袭性前病变中DNA甲基化的研究此外，我们还将研究 通过新汉普郡出生队列研究收集非肿瘤细胞的育龄妇女 从母乳和乳头抽吸液中评估DNA甲基化与风险的关系 乳腺癌的致病因素。进一步，我们将探索DNA甲基化在个体内的变化 在一组妇女中收集母乳和乳头吸液。这项工作的目标是扩展 我们对确定乳腺癌危险因素的生物学机制的理解 有助于癌症的发生，这具有广泛的潜在影响，通过以下方式影响所有乳腺癌风险人群 更好地指导现有的风险预测模型，并为乳腺癌预防提供新的战略。

Several established risk factors such as age, parity, family history and body mass index (BMl) contribute to the genesis of invasive breast cancers, the most common non-keratinocyte cancer among women in the United States. The current model of breast cancer indicates progression from normal breast to a benign lesion, noninvasive disease, and then an invasive tumor. Relationships between established breast cancer risk factors and the epigenetic character of breast tumors have begun to be described, and epigenetic alterations including DNA methylation alterations are known early contributors to breast tumorigenesis. However, the presence of epigenetic alterations that occur in the context of invasive breast cancer is underexplored along the continuum of normal breast, pre-neoplastic lesions, and non-invasive breast cancers. Our published preliminary data indicate significant, independent associations of breast tumor DNA methylation profiles with modifiable breast cancer risk factors. Here, we propose to test the hypothesis that DNA methylation variation in normal breast, pre-neoplastic lesions, and non-invasive cancers is associated with disease risk factors and progression to invasive disease. This work will leverage existing tissue and patient data resources from women enrolled in the New Hampshire Mammography Network allowing investigation of DNA methylation in benign lesions and pre-invasive disease. In addition, we will study women of child-bearing age through the New Hampshire Birth Cohort Study, collecting non-neoplastic cells from breast milk and nipple aspirate fluid to evaluate the relationships between DNA methylation and risk factors for breast cancer. Further, we will explore intraindividual changes in DNA methylation from repeated collections of breast milk and nipple aspirate fluid in a subset of women. The goal of this work is to extend our understanding of the biological mechanisms through which established breast cancer risk factors contribute to carcinogenesis, which has broad potential to impact all individuals at risk for breast cancer by better directing existing risk prediction models, and informing novel strategies for breast cancer prevention.