Genetic Susceptibility of Estrogen Induced Mammary Cancer

描述(申请人提供)：乳腺癌风险由众多基因强烈决定，其中只有几个基因已被识别。雌性ACI大鼠表现出一种独特的、由基因赋予的对172-雌二醇(E2)诱发乳腺癌的敏感性。由于雌激素与乳腺癌的病因学有着千丝万缕的联系，ACI大鼠正迅速被乳腺癌研究界广泛接受，成为一种生理上相关的模型。为了确定对E2诱导的乳腺癌易感性的遗传基础，我们对敏感的ACI株和抗性的哥本哈根(COP)或棕色挪威(BN)株进行了杂交，发现了9个显著影响乳腺癌易感性的数量性状基因座(QTL)。其中两个QTL Emca1和Emca8被定位到大鼠5号染色体的重叠区域(RNO5)，第三个QTL Emca4被定位到RNO7。这里总结的数据强烈表明，人类基因组中与这三个Emca基因座同源的区域含有尚未确定的乳腺癌易感基因。这项研究的目的是确定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生的分子机制。目的1是确定位于Emca8中的基因，这些基因决定了对E2诱导的乳腺癌的易感性。使用同源大鼠品系的替换作图方法将被用于对Emca8进行精细定位。每个同源菌株的发展将由初步数据指导，这些数据表明Emca8的遗传异质性。位于最小有效同源基因间隔内的基因的表达将在mRNA和蛋白质水平上进行评估。将为ACI和BN毒株确定最小同源基因区间上的核苷酸序列，以确定导致观察到的敏感性差异的遗传变异。目的2是确定Emca1和Emca8是否具有相同的E2诱发乳腺癌的易感性决定因素。在目标1中发现的介导Emca8对乳腺癌易感性作用的基因将在COP菌株中进行评估，以确定COP和BN大鼠菌株是否共享这些基因的等位基因。目的3是确定位于Emca4中的基因变异，该基因变异决定了对E2诱导的乳腺癌的易感性。这一目标将集中在Emca4区域，该区域与最近绘制的人类乳腺癌风险的基因决定因素同源，但尚未确定。这些拟议的研究有望极大地提高我们关于乳腺癌风险是如何由基因决定的知识，以及雌激素促进乳腺癌发生的机制。与公众健康相关：这项研究利用一种新的、生理上相关的大鼠乳腺癌模型来识别决定乳腺癌易感性的基因。由于这种模型与人类乳腺癌之间有许多相似之处，因此人们相信，这项研究中确定的基因也将同样影响人类患乳腺癌的风险。这些研究还将揭示雌激素促进乳腺癌发展的机制。

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.