WKY RAT GENETIC MODEL FOR BREAST CANCER SUSCEPTIBILITY

一个重要的新模型的研究遗传的遗传成分 乳腺癌的发病率。 该模型基于WKy大鼠品系 其几乎完全抵抗自发的和化学的（例如， 7，12-二甲基苯并蒽（DMBA）和N-亚硝基甲基脲（NMU）） 诱发乳腺癌。这是根据初步数据假设的 这种抵抗乳腺癌的基因是 由显性抗性和增强子基因相互作用控制， 所述抗性基因相对于增强子基因是上位性的。 目标 该项目的目的是识别和表征这些基因， 定位克隆主要抗性基因（可能是Mcs-4）。 的 第一个目标是从遗传学上鉴定数量性状位点（QTL）， 控制WKy对DMBA诱导的整体易感性的基因 乳腺癌这些信息将用于第二个目标， 繁殖和鉴定两种同类大鼠品系，每种都携带 主要抗性QTL或主要增强子QTL。 表征 这些同源性包括确定是否 抗性/增强子基因座以细胞自主方式发挥作用。 同类的 大鼠也将被用于目标3，以确定基因， 在同系大鼠和对照WF之间差异表达 老鼠品系。 这些基因都将提供产生假设的数据 关于基因功能和筛查候选乳腺癌的检测 易感基因 目标4将识别（通过定位克隆 方法），并评估抗性位点的候选基因（可能 Mcs-4）。 几种新的生物测定来评估这些潜力 候选人将被使用。 筛选后的候选人将使用 转基因大鼠模型。 最后，人类同源物将被克隆， 强有力的候选基因，以期待未来的人类研究。 的 我们的目标的实现可以提供：额外的洞察力和试剂 更好地估计女性患乳腺癌的遗传风险; 为开发预防乳腺癌的药物提供了目标。

An important new model for the study of the inherited genetic component of breast cancer is proposed. This model is based on the WKy rat strain which is almost completely resistant to spontaneous and chemically (e.g. 7,12-dimethylbenz(a)anthracene (DMBA) and N-nitrosomethylurea (NMU)) induced mammary carcinomas. It is hypothesized based on preliminary data that the genetics underlying this resistance to mammary cancer is controlled by interacting dominant resistance and enhancer genes with the resistance gene(s) being epistatic over enhancer gene(s). The goal of this project is to identify and characterize these genes and to positionally clone the major resistance gene (likely to be Mcs-4). The first aim is to genetically identify the quantitative trait loci (QTLs) that control the overall susceptibility of the WKy to DMBA-induced mammary carcinomas. This information will be used in the second aim to breed and characterize two congenic rat strains, each carrying either the major resistance QTL or the major enhancer QTL. Characterization of these congenics includes the determination of whether the resistance/enhancer loci act in a cell autonomous fashion. The congenic rats will also be used in Aim 3 to identify genes that are differentially expressed between the congenic rats and the control WF rat strain. These genes will both provide hypothesis-generating data regarding gene function and an assay to screen candidate breast cancer susceptibility genes. Aim 4 will identify (by a positional cloning approach) and evaluate candidate genes at the resistance locus (likely Mcs-4). Several novel biological assays to evaluate these potential candidates will be used. Screened candidates will be tested using transgenic rat models. Finally, human homologues will be cloned for strong candidate genes in anticipation of future human studies. The accomplishment of our goal may provide: additional insight and reagents to better estimate the genetic risk of women for breast cancer; and new targets for the development of drugs to prevent breast cancer.