Genetic Susceptibility of Estrogen Induced Mammary Cancer

雌激素诱发乳腺癌的遗传易感性

• 批准号: 7647984
• 负责人: JAMES D SHULL
• 金额: $ 6.93万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647984
• 关键词: Accounting; Alleles; Base Sequence; Breast Cancer Model; Cancer-Predisposing Gene; Chromosomes, Human, Pair 5; Clinic; Clinical; Communities; Congenic Strain; Data; Development; Epidemiologist; Estradiol; Estrogens; Etiology; Exhibits; Female; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Heterogeneity; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genome; Germ Lines; Goals; Haplotypes; Human; Human Chromosomes; Human Genome; Inbred ACI Rats; Knowledge; Laboratories; Laboratory Study; Location; Mammary Neoplasms; Mammary Tumorigenesis; Maps; Mediating; Messenger RNA; Methods; Modeling; Molecular; Mutation; Norway; Predisposition; Proteins; Quantitative Trait Loci; Rat Strain ACI; Rat Strains; Rattus; Rattus norvegicus; Relative (related person); Research; Resolution; Risk; Role; Series; Staging; Translating; Translational Research; Variant; anticancer research; base; cancer genome; cancer risk; congenic; genetic variant; genome wide association study; insight; malignant breast neoplasm; novel; population based; public health research; research study; resistant strain; translational study

DESCRIPTION (provided by applicant): Breast cancer risk is strongly determined by numerous genes, only a few of which have been identified. The female ACI rat exhibits a unique, genetically-conferred, susceptibility of to 172-estradiol (E2)-induced mammary cancer. Because estrogens have been inextricably implicated in the etiology of breast cancer, the ACI rat is rapidly gaining wide acceptance within the breast cancer research community as a physiologically relevant model. To define the genetic bases of susceptibility to E2-induced mammary cancer, we performed intercrosses between the susceptible ACI strain and the resistant Copenhagen (COP) or Brown Norway (BN) strains and revealed 9 quantitative trait loci (QTL) that significantly impact susceptibility to mammary cancer. Two of these QTL, Emca1 and Emca8, were mapped to an overlapping region of rat chromosome 5 (RNO5), and a third, Emca4, was mapped to RNO7. Data summarized herein strongly suggest that the regions of the human genome that are orthologous to these three Emca loci harbor as yet unidentified breast cancer susceptibility genes. The objectives of this research are to identify genes residing within Emca1, Emca4 and Emca8 that determine breast cancer risk and to define better the molecular mechanisms through which estrogens contribute to breast cancer development. Aim 1 is to identify genes residing within Emca8 that determine susceptibility to E2-induced mammary cancer. A substitution mapping approach employing congenic rat strains will be used to fine map Emca8. Development of each congenic strain will be directed by preliminary data that are indicative of genetic heterogeneity across Emca8. Expression of genes residing within a minimal effective congenic interval will be evaluated at the mRNA and protein levels. Nucleotide sequence across the minimal congenic interval will be determined for the ACI and BN strains to identify the genetic variant responsible for the observed difference in susceptibility. Aim 2 is to determine whether Emca1 and Emca8 harbor the same determinants of susceptibility to E2-induced mammary cancer. Genes identified in Aim 1 that mediate the actions of Emca8 on mammary cancer susceptibility will be evaluated in the COP strain to determine if the COP and BN rat strains share alleles for these genes. Aim 3 is to identify the genetic variant residing within Emca4 that determines susceptibility to E2-induced mammary cancer. This aim will be focused on the region of Emca4 that is orthologous to a recently mapped, but as yet unidentified, genetic determinant of breast cancer risk in humans. These proposed studies promise to greatly enhance our knowledge regarding how breast cancer risk is genetically determined, as well as to the mechanisms through which estrogens contribute to breast cancer development. Relevance to public health: This research utilizes a novel and physiologically relevant rat mammary cancer model to identify genes that determine mammary cancer susceptibility. Because of the numerous similarities between this model and breast cancer in humans, it is believe that the genes identified in this study will similarly impact breast cancer risk in humans. These studies will also reveal insight into the mechanisms through which estrogens contribute to breast cancer development.

描述（由申请人提供）：乳腺癌风险很大程度上由众多基因决定，但其中只有少数基因已被识别。雌性 ACI 大鼠对 172-雌二醇 (E2) 诱导的乳腺癌表现出独特的遗传性易感性。由于雌激素与乳腺癌的病因学有着千丝万缕的联系，ACI 大鼠作为一种生理相关模型，正在迅速获得乳腺癌研究界的广泛接受。为了确定 E2 诱导的乳腺癌易感性的遗传基础，我们在易感 ACI 菌株和耐药性哥本哈根 (COP) 或布朗挪威 (BN) 菌株之间进行了杂交，并揭示了 9 个显着影响乳腺癌易感性的数量性状位点 (QTL)。其中两个 QTL Emca1 和 Emca8 被定位到大鼠 5 号染色体 (RNO5) 的重叠区域，第三个 QTL Emca4 被定位到 RNO7。本文总结的数据强烈表明，与这三个 Emca 基因座直系同源的人类基因组区域含有尚未鉴定的乳腺癌易感基因。本研究的目的是确定 Emca1、Emca4 和 Emca8 中决定乳腺癌风险的基因，并更好地确定雌激素促进乳腺癌发展的分子机制。目标 1 是鉴定 Emca8 内的基因，这些基因决定对 E2 诱导的乳腺癌的易感性。采用同源大鼠品系的替代作图方法将用于精细图谱 Emca8。每个同源菌株的开发将由表明 Emca8 遗传异质性的初步数据指导。将在 mRNA 和蛋白质水平上评估位于最小有效同源区间内的基因的表达。将确定 ACI 和 BN 菌株跨最小同源区间的核苷酸序列，以鉴定导致观察到的易感性差异的遗传变异。目标 2 是确定 Emca1 和 Emca8 是否具有相同的 E2 诱导乳腺癌易感性决定因素。目标 1 中鉴定的介导 Emca8 对乳腺癌易感性作用的基因将在 COP 品系中进行评估，以确定 COP 和 BN 大鼠品系是否共享这些基因的等位基因。目标 3 是鉴定 Emca4 内的遗传变异，该变异决定 E2 诱导的乳腺癌的易感性。这一目标将集中于 Emca4 区域，该区域与最近绘制但尚未确定的人类乳腺癌风险遗传决定因素是同源的。这些拟议的研究有望大大增强我们对乳腺癌风险如何由基因决定以及雌激素促进乳腺癌发展的机制的了解。与公共卫生的相关性：本研究利用一种新颖且生理相关的大鼠乳腺癌模型来识别决定乳腺癌易感性的基因。由于该模型与人类乳腺癌之间有许多相似之处，因此相信本研究中确定的基因也会同样影响人类乳腺癌风险。这些研究还将揭示雌激素促进乳腺癌发展的机制。