Genetic modifiers of mammary tumor susceptibility

描述(申请人提供)：乳腺癌是一种复杂的疾病，环境和遗传因素都会导致个人患上疾病的风险。TP53的可遗传突变与Li-Fraumeni综合征有关，在Li-Fraumeni综合征中，乳腺癌是最常见的肿瘤。Li-Fraumeni综合征的小鼠模型也显示出频繁的乳腺肿瘤，但取决于遗传背景。BM-BLC-Trp53/-小鼠(易感)和C57BU6-Trp5y‘~小鼠(耐药)之间乳腺肿瘤发病率的差异使我们能够研究改变乳腺肿瘤易感性的遗传机制。我们已经证明了隐性作用和显性作用的易感等位基因都有助于乳腺癌的易感性。一个隐性作用的乳腺肿瘤抑制基因(SuprMaml)已被定位到小鼠7号染色体的10Mb区域。相反，重组途径介导了乳腺肿瘤中Trp53杂合性的丢失，并作为显性性状遗传。因此， Balb/c等位基因似乎干扰了DNA双链断裂同源定向修复的速率或保真度。这些观察为确定影响小鼠对乳腺肿瘤易感性的基因和途径提供了一种手段。 具体目的1：分析Dmbtl对乳腺肿瘤的抑制作用。目的1.1：探讨Dmbt1作为肿瘤抑制基因的作用。表达构建体将被引入乳腺上皮细胞系中，并将监测肿瘤发病率的变化。目的：检测DMBT1蛋白在正常乳腺组织和肿瘤组织中的表达，探讨DMBT1作为生物标志物的价值。 具体目的2：对乳腺肿瘤发生的影响进行遗传学解剖。目的2.1：利用同源基因小鼠，研究SuprMaml基因座对乳腺肿瘤发病率的抑制作用。目的2.2：该间隔将在不同的同源基因小鼠中细分，以精炼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物。遗传背景可能通过改变DNA修复的速率或保真度来影响对乳腺肿瘤的易感性。因此，DNA双链断裂修复的速度将使用合成底物进行监测。 识别改变乳腺癌易感性的基因将为风险评估提供标记，并为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.