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。这种遗传病因大多是由低外显率、高频修饰基因驱动的。该项目的目标是开始识别和表征这些修饰基因。提出了一种使用大鼠乳腺癌模型来帮助确定这种遗传病因的复杂性和确定乳腺癌易感基因的策略。具体来说，本项目的重点是乳腺癌抗性WKy大鼠菌株，其中5个控制乳腺癌的基因位点已被遗传鉴定。其中两个基因座，Mcs5，一个抗性修饰位点，和Mcs7，一个增加的易感性位点，将是这个项目的重点。对于Mcs5和Mcs7，重组基因大鼠将被培育（将WKy等位基因转移到WF背景），使每个Mcs位点（亚位点）间隔低于2 cM。在这个区间内的基因将被鉴定和表征WKy和WF大鼠之间的基因表达和序列差异。同源大鼠将通过确定：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来表征这些基因座。此外，候选基因在最小同源区域内的有效性将使用转基因大鼠进行评估。Mcs7 QTL位点也与乳腺癌中的等位基因失衡（AI）有关。QTL和AI是否由同一基因驱动还有待确定。预计将在这两个qtl中发现至少两到三个基因并进行鉴定。在未来，通过基于snp的乳腺癌病例对照关联研究，通过询问女性中是否存在类似作用的同源等位基因，该项目中产生的知识可用于转化为女性。

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.