Genetics of Breast Cancer Risk at Windows of Exposure

描述（由申请人提供）：女性个体对乳腺癌的易感性是由其遗传易感性和个人环境以及基因与环境因素之间和内部的相互作用决定的。环境也是复杂的，既有内生因素，也有外生因素。重要的是，在乳腺癌中，对环境因子的易感性高度依赖于暴露时乳房的生理和发育状态，即易感性窗口。女性一生中几个主要的激素里程碑影响乳房的发育状态和调节易感性。这项提议将集中在三个产后窗口的乳腺癌易感性使用大鼠和人类的研究。在大鼠中，这些窗口包括“未成熟”窗口（3周龄大鼠），对应于人类的童年，“青春期”窗口（7周龄大鼠），以及新的“老年成人”窗口（65周龄大鼠），对应于女性的绝经期。据推测，环境诱发乳腺癌的易感性是由窗口特异性风险等位基因/基因调节的。从这些大鼠模型中获得的结果将使用侧重于遗传流行病学调查的比较基因组学方法扩展到女性。目的1将确定七个先前确定的乳腺癌易感性（Mcs）等位基因，这些等位基因已被证明在青少年窗口期调节乳腺癌风险，是该窗口期独有的，还是也将在未成熟或老年窗口期发挥作用。Aim 2a将通过整合腺体形态和全局基因表达，对所有三个窗口的乳腺进行表型分析。目的2b和2c将询问暴露在不同窗口诱导的乳腺癌是否表现出窗口特异性的基因表达和通路信号模式。这些表达模式将与人类乳腺癌基因表达模式进行比较。目标3将通过基因鉴定独特的定量风险位点（QTL）来扩展先前目标的工作，这些位点在青春期窗口不活跃，但在其他两个窗口调节风险。目标4将侧重于对7000多名女性进行比较基因组学/分子流行病学病例对照研究，以确定与我们的位点（目标1）和QTL（目标3）同源的人类区域中已建立和疑似GWAS snp。重要的是，所有主要的研究计划都将包括威斯康星州内几个倡导和社区团体的合作伙伴的投入（目标5）。倡导者和科学家将共同交流这些研究以及其他BCERP合作者的重要研究结果。

DESCRIPTION (provided by applicant): An individual woman's susceptibility to breast cancer is determined by her inherited genetic susceptibility and her personal environment as well as interactions between and within genes and environmental factors. The environment is also complex, consisting of both endogenous and exogenous factors. Importantly, in breast cancer, the susceptibility to environmental agents is highly dependent on the physiological and developmental status of the breast at the time of exposure, i.e., windows of susceptibility. Several major hormonal landmarks in a woman's life impact on the breast's developmental status and modulate susceptibility. This proposal will focus on three post-natal windows of breast cancer susceptibility using both rat and human studies. In rats, these windows include the "immature" window (3 week old rats) corresponding to childhood in humans, the "adolescent" window (7 week old rats), and the novel "older adult" window (65 week old rats) corresponding to peri- menopause in women. It is hypothesized that susceptibility to environmental induced breast cancer is modulated by window-specific risk alleles/genes. Results obtained from these rat models will be extended to women using a comparative genomics approach focusing on genetic epidemiological investigations. Aim 1 will determine if seven previously identified mammary carcinoma susceptibility (Mcs) alleles that have been shown to modulate mammary cancer risk at the adolescent window are unique for this window or will also function at the immature or older adult windows. Aim 2a will phenotype mammary gland at all three windows by integrating gland morphology with global gene expression. Aims 2b and 2c will ask if mammary carcinomas induced by exposure at different windows show window-specific patterns of gene expression and pathway signaling. These expression patterns will be compared to human breast cancer gene expression patterns. Aim 3 will extend work on previous aims by genetically identifying unique quantitative risk loci (QTL) that are not active at the adolescent window but modulate risk at the other two windows. Aim 4 will focus on a comparative genomics/molecular epidemiologic case-control study of over 7,000 women to identify established and suspected GWAS SNPs in human regions homologous to our loci (Aim 1) and QTL (Aim 3). Importantly, all major study planning will include input from partners affiliated with several advocacy and community groups within Wisconsin (Aim 5). Advocates and scientists will jointly communicate important results from these studies as well as studies from other BCERP collaborators.