Genetic modifiers of mammary tumor susceptibility

乳腺肿瘤易感性的遗传修饰

• 批准号: 7359638
• 负责人: D. Joseph Jerry
• 金额: $ 28.64万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7359638
• 关键词: Alleles; Biological Markers; Cancer Patient; Cell Line; Chromosomes, Human, Pair 7; Common Neoplasm; Complex; Computer Simulation; Congenic Mice; Control Groups; DMBT1 gene; DNA Double Strand Break; DNA Repair; Disease; Dissection; Dominant Genetic Conditions; Double Strand Break Repair; Epithelial Cells; Exhibits; Gene-Modified; Genes; Genetic; Genetic Recombination; Haplotypes; Human; Inbred BALB C Mice; Incidence; Individual; Inherited; Li-Fraumeni Syndrome; Location; Loss of Heterozygosity; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Maps; Mediating; Monitor; Mus; Mutation; Neoplasm Transplantation; Numbers; Pathway interactions; Predisposition; Procedures; Rate; Research Personnel; Resistance; Risk; Risk Assessment; Staging; TP53 gene; Therapeutic Intervention; Tumor Suppressor Genes; Tumor Suppressor Proteins; Woman; base; glycoprotein 340; homologous recombination; malignant breast neoplasm; mouse model; novel; programs; repaired; tumor; tumor progression

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.

描述（由申请人提供）：乳腺癌是一种复杂的疾病，具有环境和遗传因素，导致个人患疾病的风险。 TP53中可遗传的突变与乳腺癌是最常见的肿瘤的Li-Fraumeni综合征有关。 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-TRP53 +/-小鼠（易感）和C57BU6-TRP5Y'〜小鼠（抗药性）之间乳腺肿瘤的发病率差异使我们能够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敏感性等位基因有助于乳腺肿瘤的敏感性。充当抑制乳腺肿瘤（SuprMAML）抑制剂的隐性作用基因座已映射到小鼠染色体7的10 MB区域。相反，相比之下，一种重组途径介导的乳腺肿瘤中TRP53的杂合性丧失，并被遗传为占主导地位的特征。所以， BALB/C等位基因似乎干扰了DMA双链断裂的同源指导修复的速率或保真度。这些观察结果提供了一种鉴定影响小鼠乳腺肿瘤易感性的基因和途径的方法。 具体目标1：分析DMBTL在抑制乳腺肿瘤中的影响。 AIM 1.1：将检查DMBTL作为肿瘤抑制基因的影响。表达构建体将被引入乳腺上皮细胞系中，并将监测肿瘤发生率的变化。 AIM 1.2：将确定DMBT1蛋白在正常的人乳腺组织和肿瘤中的表达，以评估DMBT1作为生物标志物的值。 特定目标2：Suprmaml基因座对乳腺肿瘤发生率的遗传解剖。 AIM 2.1：将在先天小鼠中确定SuprMAML基因座对乳腺肿瘤发生率的肿瘤抑制作用的大小。 AIM 2.2：间隔将在单独的先天小鼠中细分，以完善肿瘤抑制活性的位置。 特定目的3：分析主要的作用修饰符，以改变DNA双链断裂的修复速率。遗传背景可能会通过改变DNA修复的速率或保真度来影响对乳腺肿瘤的敏感性。因此，将使用合成底物监测DNA双链断裂修复的速率。 鉴定改变乳腺肿瘤易感性的基因将为风险评估和治疗干预的新目标提供标记。