Genetics of Breast Cancer Risk at Windows of Exposure

暴露窗口期乳腺癌风险的遗传学

• 批准号: 8011251
• 负责人: MICHAEL N GOULD
• 金额: $ 44.55万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011251
• 关键词: Adolescent; Advocacy; Advocate; Alleles; Archives; Breast; Breast Carcinoma; Case-Control Studies; Childhood; Communication; Communities; Complex; County; DNA; Data; Development; Elderly; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Exogenous Factors; Family history of; Fostering; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Geographic Locations; Gland; Hormonal; Human; Incidence; Individual; Inherited; Investigation; Life; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Menopause; Modeling; Molecular; Morphology; Participant; Pattern; Phenotype; Physiological; Population; Predisposition; Principal Investigator; Rattus; Research; Research Personnel; Risk; Risk Factors; Sampling Studies; Scientist; Signal Pathway; Single Nucleotide Polymorphism; Structure; Telephone Interviews; Time; Validation; Wisconsin; Woman; Work; cancer gene expression; cancer genome; cancer risk; case control; comparative genomics; environmental agent; genome wide association study; malignant breast neoplasm; meetings; member; novel; population based; programs; reproductive

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.

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。环境也是复杂的，既有内源因素，也有外源因素。 重要的是，在乳腺癌中，对环境因素的敏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。女性一生中的几个主要荷尔蒙标志会影响乳房的发育状态并调节敏感性。该提案将通过大鼠和人体研究重点关注乳腺癌易感性的三个产后窗口。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）和对应于女性围绝经期的新型“老年”窗口（65周龄大鼠）。据推测，对环境诱发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。目标 1 将确定先前确定的 7 个乳腺癌易感性 (Mcs) 等位基因是否在青少年窗口期具有调节乳腺癌风险的作用，或者是否也在未成熟或老年窗口期发挥作用。目标 2a 将通过将腺体形态与整体基因表达相结合，在所有三个窗口对乳腺进行表型分析。目标 2b 和 2c 将询问不同窗口暴露诱发的乳腺癌是否表现出窗口特异性的基因表达和通路信号传导模式。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，这些位点在青少年窗口不活跃，但在其他两个窗口调节风险。 目标 4 将侧重于对 7,000 多名女性进行比较基因组学/分子流行病学病例对照研究，以确定与我们的基因座（目标 1）和 QTL（目标 3）同源的人类区域中已确定的和可疑的 GWAS SNP。重要的是，所有主要研究计划都将包括威斯康星州内多个倡导和社区团体附属合作伙伴的意见（目标 5）。倡导者和科学家将共同交流这些研究以及其他 BCERP 合作者的研究的重要结果。