Genetic modifiers of mammary tumor susceptibility

描述（由申请人提供）：乳腺癌是一种复杂的疾病，环境和遗传因素都有助于个体发生疾病的风险。TP 53的遗传突变与Li-Fraumeni综合征有关，其中乳腺癌是最常见的肿瘤。Li-Fraumeni综合征的小鼠模型也表现出频繁的乳腺肿瘤，但取决于遗传背景。BM-Blc-Trp 53 +/-小鼠（易感）和C57 BU 6-Trp 53 +/-小鼠（抗性）之间乳腺肿瘤发病率的差异允许我们研究改变对乳腺肿瘤易感性的遗传机制。我们已经证明隐性作用和显性作用易感性等位基因都有助于乳腺肿瘤易感性。作为乳腺肿瘤抑制因子的隐性作用基因座（SuprMaml）已定位于小鼠7号染色体的10 Mb区域。与此相反，重组途径介导的杂合性丢失在Trp 53在乳腺肿瘤和遗传作为一个显性性状。因此，我们认为， BALB/c等位基因似乎干扰DNA双链断裂的同源定向修复的速率或保真度。这些观察结果提供了一种手段，以确定影响小鼠乳腺肿瘤易感性的基因和途径。 具体目的1：分析Dmbtl在抑制乳腺肿瘤中的作用。目的1.1：将检查Dmbtl作为肿瘤抑制基因的作用。将表达构建体引入乳腺上皮细胞系，并监测肿瘤发生率的变化。目的1.2：检测DMBT 1蛋白在正常人乳腺组织和肿瘤中的表达，以评估DMBT 1作为生物标志物的价值。 具体目标2：SuprMaml基因座对乳腺肿瘤发病率的影响的遗传解剖。目的2.1：将使用同类小鼠确定SuprMaml基因座对乳腺肿瘤发生率的肿瘤抑制作用的大小。目的2.2：将在单独的同类小鼠中细分间隔，以细化肿瘤抑制活性的位置。 具体目标3：分析改变DNA双链断裂修复速率的显性作用修饰剂。遗传背景可能通过改变DNA修复的速率或保真度来影响乳腺肿瘤的易感性。因此，将使用合成底物监测DNA双链断裂修复速率。 对改变乳腺肿瘤易感性的基因的鉴定将为风险评估和治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): Breast cancer is a complex disease with both environmental and genetic factors contributing to an individual's risk of developing disease. Heritable mutations in TP53 have been associated with Li-Fraumeni syndrome in which breast cancer is the most common tumor. Mouse models of Li-Fraumeni syndrome also exhibit frequent mammary tumors, but depend on the genetic background. The difference in incidence of mammary tumors between BM-Blc-Trp53 +/- mice (susceptible) and C57BU6-Trp5y'~ mice (resistant) has allowed us to investigate genetic mechanisms that modify susceptibility to mammary tumors. We have demonstrated that both recessive-acting and dominant-acting susceptibility alleles contribute to mammary tumor susceptibility. A recessive-acting locus that acts as a suppressor of mammary tumors (SuprMaml) has been mapped to a 10 Mb region of mouse chromosome 7. In contrast, a recombination pathway mediated loss of heterozygosity at Trp53 in mammary tumors and was inherited as a dominant trait. Therefore, BALB/c alleles appear to interfere with rates or fidelity of homology-directed repair of DMA double strand breaks. These observations provide a means to identify genes and pathways that influence susceptibility to mammary tumors in mice. Specific Aim 1: Analysis of the effect of Dmbtl in suppression of mammary tumors. Aim 1.1: The effects of Dmbtl as a tumor suppressor gene will be examined. Expression constructs will be introduced into mammary epithelial cell lines and changes in tumor incidence will be monitored. Aim 1.2: Expression of DMBT1 protein in normal human breast tissues and tumors will be determined to assess the value of DMBT1 as a biomarker. Specific Aim 2: Genetic dissection of the effects of the SuprMaml locus on incidence of mammary tumors. Aim 2.1: The magnitude of the tumor suppressive effect of the SuprMaml locus on incidence of mammary tumors will be determined using in congenic mice. Aim 2.2: The interval will be subdivided in separate congenic mice to refine the location of the tumor suppressor activity. Specific Aim 3: Analysis of dominant-acting modifiers that alter rates of repair of DNA double strand breaks. Genetic background may influence susceptibility to mammary tumors by altering the rates or fidelity of DNA repair. Therefore, rates of DNA double strand break repair will be monitored using synthetic substrates. Identification of genes that modify susceptibility to mammary tumors will provide markers for risk assessment and novel targets for therapeutic intervention.