WKy Rat Genetic Model for Breast Cancer Susceptibility

描述（由申请人提供）：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。这种遗传病因学的大部分是由低频率、高频率的修饰基因驱动的。这个项目的目标是开始识别和表征这样的修饰基因。提出了一种使用大鼠乳腺癌模型来帮助定义这种遗传病因学的复杂性和识别乳腺癌易感基因的策略。具体而言，该项目侧重于乳腺癌抗性WKy大鼠品系，其中已从遗传学上鉴定出控制乳腺癌的五个基因座。其中两个位点，Mcs5，抗性修饰剂，和Mcs7，增加易感性位点，将是这个项目的重点。对于Mcs5和Mcs7，将繁殖重组同源大鼠（WKy等位基因转移至WF背景），以使每个Mcs基因座（亚基因座）间隔低于2 cM。将鉴定该区间内的基因，并表征WKy和WF大鼠之间的基因表达和序列差异。将使用同源大鼠通过确定以下参数来表征这些基因座：a）其细胞自主性状态，B）其相关乳腺组织病理学，c）其对乳腺基因表达的影响，以及d）其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价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不平衡（AI）相关，其在乳腺癌中的人类同源区域也是如此。将确定是否相同的基因驱动QTL和AI两者。这两个QTL中至少有两到三个基因的发现和鉴定是有希望的。在未来，在这个拟议的项目中产生的知识可以用来翻译到女性，通过询问是否有类似的作用同源等位基因存在于女性使用基于SNP的乳腺癌病例对照关联研究。

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.