Genetic Susceptibility of Estrogen Induced Mammary Cancer

描述（由申请人提供）：乳腺癌的风险是由许多基因，其中只有少数已被确定。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大鼠作为一种生理学相关模型在乳腺癌研究界迅速获得广泛认可。为了确定E2诱导的乳腺癌易感性的遗传基础，我们进行了易感ACI株和抗性哥本哈根（COP）或布朗挪威（BN）株之间的杂交，并揭示了9个数量性状位点（QTL），显着影响乳腺癌的易感性。其中两个QTL，Emca 1和Emca 8，被定位到大鼠5号染色体（RNO 5）的重叠区域，第三个，Emca 4，被定位到RNO 7。本文总结的数据有力地表明，人类基因组中与这三个Emca基因座正交的区域含有尚未鉴定的乳腺癌易感基因。这项研究的目的是确定Emca 1，Emca 4和Emca 8中决定乳腺癌风险的基因，并更好地定义雌激素促进乳腺癌发展的分子机制。目的1是确定Emca 8中决定E2诱导的乳腺癌易感性的基因。采用同类大鼠品系的替代作图方法将用于精细作图Emca 8。每种同源菌株的开发将由指示Emca 8间遗传异质性的初步数据指导。将在mRNA和蛋白质水平评价最小有效同源间隔内的基因表达。将确定ACI和BN菌株最小同源间隔的核苷酸序列，以鉴定导致观察到的敏感性差异的遗传变异。目的2是确定Emca 1和Emca 8是否具有相同的E2诱导的乳腺癌易感性决定因素。将在COP品系中评价目的1中鉴定的介导Emca 8对乳腺癌易感性作用的基因，以确定COP和BN大鼠品系是否共享这些基因的等位基因。目的3是确定Emca 4中决定E2诱导的乳腺癌易感性的遗传变异。这一目标将集中在Emca 4区域，该区域与最近绘制的但尚未鉴定的人类乳腺癌风险遗传决定因素相关。这些拟议的研究有望大大提高我们对乳腺癌风险如何由遗传决定的知识，以及雌激素促进乳腺癌发展的机制。与公共卫生的相关性：本研究利用一种新的生理学相关的大鼠乳腺癌模型来鉴定决定乳腺癌易感性的基因。由于该模型与人类乳腺癌之间存在许多相似之处，因此相信本研究中确定的基因将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。

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.