Genomic Basis of Reproductive History on Breast Cancer

描述（由申请人提供）：虽然导致乳腺癌的药物和机制仍不确定，但有大量证据表明，乳腺癌的风险强烈依赖于内分泌和生殖条件，如初潮早、绝经晚和不孕。另一方面，早期的第一次足月妊娠可以提供终身保护。通过实验，我们已经证明，怀孕所赋予的保护是通过诱导乳房分化介导的，这表现在小叶发育、细胞增殖和类固醇激素受体含量的减少，以及与化学诱导癌变的难治性相关的“基因组特征”。该应用程序提出了一个假设，即早期怀孕在乳房中留下永久性的基因组变化，从而降低患乳腺癌的终生风险。这一假设将通过以下具体目标来证明：1：表征由于生殖史而患乳腺癌“低”和“高”风险的妇女的特定基因表达谱。将有一次或多次早期足月妊娠史的绝经后妇女正常乳腺组织中的基因表达与未生育的绝经后妇女正常乳腺组织中的基因表达进行比较。为此，我们将使用现有的人类cDNA文库进行基因表达的大规模分析，以确定已知和未知（ESTs）基因的表达模式。2：确定由于生殖史（在特定目的1中确定）而有患乳腺癌风险的妇女中差异表达的基因簇在绝经后乳腺癌妇女的乳房问题中与未患乳腺癌的绝经后妇女相比是否存在差异表达。为此，我们将进行一项病例对照研究，比较患有侵袭性乳腺癌的绝经后妇女与患有良性乳腺疾病的绝经后妇女正常乳腺组织中的基因表达谱。通过这些研究获得的知识将使我们能够识别由早孕引起的“基因组特征”，如果被证明与功能相关，将作为评估大规模人群乳腺癌风险的分子标记。

DESCRIPTION (provided by applicant): Although the agents and the mechanisms that cause breast cancer are still uncertain, there is substantial evidence that breast cancer risk is strongly dependent on endocrinological and reproductive conditions, such as early menarche, late menopause, and nulliparity. An early first full term pregnancy, on he other hand, confers a lifetime protection. Experimentally we have demonstrated that the protection conferred by pregnancy is mediated by induction of breast differentiation, which is manifested through obular development, reduced cell proliferation and steroid hormone receptor content, and a "genomic signature" that is associated with refractoriness to chemically induced carcinogenesis. This application proposes to test the hypothesis that early pregnancy imprints in the breast permanent genomic changes that reduce the lifetime risk of the developing breast cancer. This hypothesis will be demonstrated through the following specific aims: 1: To characterize the specific gene expression profile of women at "low" and 'high" risk of developing breast cancer because of reproductive history. Gene expression in normal breast tissue obtained from postmenopausal women with a history of one or more early full term pregnancies will he compared to gene expression in normal breast tissue from postmenopausal women who are nulliparous. For this purpose we will perform a large-scale analysis of gene expression using available human cDNA libraries for determining the expression pattern of known and unknown (ESTs) genes. 2: To determine if gene clusters differentially expressed in women at risk of developing breast cancer because of reproductive history (identified in Specific aim 1) are differentially expressed in the breast issue of postmenopausal women with breast cancer compared to postmenopausal women who do not have breast cancer. For this purpose we will perform a case-control study to compare gene expression profiles in the normal, breast tissue of postmenopausal women with invasive breast cancer vs. postmenopausal women with benign breast disease. Knowledge gained through these studies will allow us to identify the "genomic signature" induced by an early pregnancy, and that if proven to be functionally relevant would serve as molecular markers for assessing breast cancer risk in large populations.