Genetic modifiers of mammary tumor susceptibility

乳腺癌是一种复杂的疾病，环境和遗传因素都有助于个体的风险， 发展疾病。TP 53中的遗传性突变与Li-Fraumeni综合征相关，其中乳腺癌 癌症是最常见的肿瘤。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小鼠乳腺肿瘤发生率的差异 C57 BU 6-Trp 5 γ-小鼠（易感）和C57 BU 6-Trp 5 γ-小鼠（抗性）的研究使我们能够研究修饰 对乳腺肿瘤的易感性我们已经证明隐性作用和显性作用易感性 等位基因有助于乳腺肿瘤易感性。一个作为乳腺癌抑制基因的隐性作用基因座， 肿瘤（SuprMam 1）的基因定位于小鼠7号染色体的10 Mb区域。相反， 在乳腺肿瘤中Trp 53的杂合性缺失是一种显性遗传。因此，我们认为， BALB/c等位基因似乎与DNA双链断裂的同源定向修复的速率或保真度相关。这些 观察提供了一种方法来识别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抑制乳腺肿瘤的作用。目的1.1：Dmbtl的作用 作为肿瘤抑制基因将被检测。将表达构建体引入乳腺上皮细胞中， 细胞系和肿瘤发生率的变化将被监测。目的1.2：DMBT 1蛋白在正常人中的表达 将测定乳腺组织和肿瘤以评估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：SuprMaml基因座对乳腺肿瘤发病率的肿瘤抑制作用的大小将 在同类小鼠中测定。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而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。 鉴定改变对乳腺癌易感性的基因将为风险评估提供标志物 and novel新targets目标for therapeutic治疗intervention干预.

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, butdepends onthe geneticbackground. The differencein incidenceof mammarytumors betweenBM-Blc-Trp53*'~ mice (susceptible) and C57BU6-Trp5y'~ mice (resistant) has allowed us to investigate genetic mechanisms that modify susceptibility to mammarytumors. We havedemonstrated that bothrecessive-acting anddominant-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 inmammarytumors andwas inherited as adominant trait. Therefore, BALB/c alleles appear to interferewith rates or fidelity of homology-directed repair of DMA double strand breaks. These observations provide a means to identify genes and pathwaysthat influence susceptibility to mammary tumors in mice. SpecificAim 1:Analysis of the effect of Dmbtlinsuppression of mammarytumors.Aim1.1: The effects ofDmbtl as a tumor suppressor gene will be examined. Expression constructs will be introduced into mammary epithelial cell lines andchanges intumor incidence will bemonitored. Aim 1.2: Expressionof DMBT1 protein innormal 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 ofthe 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 mammarytumors byaltering the rates or fidelity of DNArepair. Therefore, rates of DNA double strand break repair will be monitored using synthetic substrates. Identificationofgenes thatmodifysusceptibilitytomammarytumors willprovidemarkers for riskassessment andnovel targets for therapeutic intervention.