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取决于她的遗传易感性和她的个人环境，以及基因和环境因素之间和内部的相互作用。环境也很复杂，既有内源性因素，也有外源性因素。 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，敏感性窗口女性生命中的几个主要激素标志影响乳房的发育状态并调节易感性。该提案将使用大鼠和人类研究重点关注乳腺癌易感性的三个出生后窗口。在大鼠中，这些窗口包括对应于人类童年的“未成熟”窗口（3周龄大鼠）、“青春期”窗口（7周龄大鼠）和对应于女性更年期的新的“老年”窗口（65周龄大鼠）。据推测，对环境诱导的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。从这些大鼠模型获得的结果将扩大到妇女使用比较基因组学的方法，重点是遗传流行病学调查。目的1将确定7个先前确定的乳腺癌易感性（MC）等位基因，这些等位基因已被证明在青春期窗口调节乳腺癌风险，是否在此窗口中是唯一的，或者也将在未成熟或老年人窗口中发挥作用。目的2a将乳腺形态学与整体基因表达相结合，在所有三个窗口进行乳腺表型。目标2b和2c将询问在不同窗口暴露诱导的乳腺癌是否显示基因表达和通路信号传导的窗口特异性模式。将这些表达模式与人乳腺癌基因表达模式进行比较。目标3将通过遗传鉴定在青少年窗口不活跃但在其他两个窗口调节风险的独特数量风险位点（QTL）来扩展先前目标的工作。 目标4将集中在一个比较基因组学/分子流行病学病例对照研究超过7,000名妇女，以确定建立和疑似GWAS SNP在人类区域同源我们的基因座（目标1）和QTL（目标3）。重要的是，所有主要研究计划将包括附属于威斯康星州内几个宣传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的重要结果以及BCERP其他合作者的研究。

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.