WKy Rat Genetic Model for Breast Cancer Susceptibility

描述(申请人提供)：乳腺癌是一种多基因疾病。这种疾病的病因至少有30%的遗传成分。这种遗传病因很大程度上是由低外显性、高频修饰基因驱动的。这个项目的目标是开始识别和表征这种修饰基因。提出了一种利用大鼠乳腺癌模型来帮助确定这种遗传病因的复杂性和识别乳腺癌易感基因的策略。具体地说，该项目关注的是耐乳腺癌的WKY大鼠品系，在该品系中，已从基因上确定了五个控制乳腺癌的基因座。其中两个基因座，Mcs5，一种抗性修饰基因，和Mcs7，一种增加的易感基因座，将是这个项目的重点。对于Mcs5和Mcs7，将培育重组同源大鼠(WKY等位基因转移到WF背景)，使每个MCS基因座(亚基因座)的间隔小于2 cM。WKY大鼠和WF大鼠之间的基因表达和序列差异将被识别和表征。同源基因大鼠将被用来确定这些基因座的特征：a)它们的细胞自主状态，b)它们相关的乳腺组织病理学，c)它们对乳腺基因表达的影响，以及d)它们对其他致癌物和癌基因的易感性。此外，将使用转基因大鼠评估最小同源区域内候选基因的有效性。Mcs7 QTL基因座也与等位基因失衡(AI)有关，在乳腺癌中其人类同源区域也是如此。这将被确定是否同一个基因(S)同时驱动QTL和AI。这两个QTL中至少有两到三个基因的发现和鉴定是可望的。在未来，这个拟议项目中产生的知识可以通过使用基于SNP的乳腺癌病例对照关联研究来询问女性中是否存在行为相似的同源等位基因，从而将其转化为女性。

DESCRIPTION (provided by applicant): Breast cancer is a multigenic disease. The etiology of this disease has at minimum a 30% genetic component. Much of this genetic etiology is driven by Iow-penetrance, high-frequency modifier genes. The goal of this project is to begin to identify and characterize such modifier genes. A strategy using rat mammary cancer models to help define the complexity of this genetic etiology and identify breast cancer susceptibility genes is proposed. Specifically, this project focuses on the mammary cancer resistant WKy rat strain in which five loci controlling mammary cancer have been genetically identified. Two of these loci, Mcs5, a resistance modifier, and Mcs7, an increased susceptibility locus, will be the focus of this project. For both Mcs5 and Mcs7, recombinant congenic rats will be bred (with the WKy allele transferred to the WF background) so that each Mcs locus (sub-locus) interval is below 2 cM. Genes within this interval will be identified and characterized for gene expression and sequence differences between WKy and WF rats. Congenic rats will be used to characterize these loci by determining: a) their cell autonomy status, b) their associated mammary histopathology, c) their effects on mammary gene expression, and d) their susceptibility to other carcinogens and oncogenes. In addition, the validity of candidate genes within the minimal congenic region will be evaluated using transgenic rats. The Mcs7 QTL locus is also associated with allelic imbalance (AI) as is its human homologous region in breast cancers. It will be determined whether the same gene(s) is driving both the QTL and the AI. The discovery and characterization of at least two to three genes within these two QTLs are expected. In the future, the knowledge generated in this proposed project can be used to translate to women by asking if similarly-acting homologous alleles exist in women using a SNP-based breast cancer case-control association study.