Early Risk Factor Related Epigenetic Alterations in Breast Cancer Pathogenesis

几个确定的风险因素，如年龄、产次、家族史和体重指数（BMI），有助于 浸润性乳腺癌的发生，这是世界上妇女中最常见的非角质细胞癌， 美国的目前的乳腺癌模型表明从正常乳腺进展为良性乳腺癌， 病变，非侵袭性疾病，然后是侵袭性肿瘤。乳腺癌与乳腺癌的关系 乳腺肿瘤的危险因素和表观遗传特征已经开始被描述， 包括DNA甲基化改变在内的改变是已知的乳腺肿瘤发生的早期因素。 然而，在浸润性乳腺癌的背景下发生的表观遗传学改变的存在， 沿着正常乳腺、癌前病变和非侵入性乳腺的连续体探索不足 癌的我们发表的初步数据表明，乳腺肿瘤DNA 甲基化谱与可改变的乳腺癌风险因素。在这里，我们提出测试的假设， 正常乳腺癌、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， 来自新罕布什尔州乳腺X线摄影网络的女性患者数据资源， 良性病变和浸润前疾病DNA甲基化研究此外，我们将研究 通过新罕布什尔州出生队列研究，收集非肿瘤细胞， 从母乳和乳头抽吸液中提取DNA，以评估DNA甲基化与风险之间的关系。 乳腺癌的病因此外，我们将探讨DNA甲基化的个体内变化， 在一部分妇女中收集母乳和乳头吸出液。这项工作的目标是扩大 我们对乳腺癌危险因素的生物学机制的理解 有助于致癌作用，这有广泛的潜力影响所有有乳腺癌风险的个体， 更好地指导现有的风险预测模型，并为预防乳腺癌的新战略提供信息。

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.