Genetic modifiers of mammary tumor susceptibility

乳腺肿瘤易感性的遗传修饰

基本信息

批准号：
7740940
负责人：
D. Joseph Jerry
金额：
$ 6.53万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
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/7740940
关键词：
Alleles Biological Markers Cancer Patient Cell Line Chromosomes, Human, Pair 7 Common Neoplasm Complex Computer Simulation Congenic Mice DMBT1 gene DNA Double Strand Break Disease Dissection Double Strand Break Repair Epithelial Cells Exhibits 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 Pathway interactions Predisposition Procedures Research Personnel Resistance Risk Staging TP53 gene Therapeutic Intervention Tumor Suppressor Genes Tumor Suppressor Proteins Woman base glycoprotein 340 homologous recombination malignant breast neoplasm mouse model programs repaired resistance allele trait tumor tumor progression

项目摘要

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.

乳腺癌是一种复杂的疾病，环境和遗传因素都导致个人的风险发展疾病。 TP53中的可遗传突变与乳房综合征有关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，但是依赖于基因背景。 BM-BLC-TRP53*'〜小鼠之间的乳腺肿瘤发生率的差异（敏感）和C57BU6-TRP5Y'〜小鼠（耐药）使我们能够研究修改的遗传机制对哺乳动物的敏感性。我们认为，不必要的作用和作用易感性等位基因有助于乳腺肿瘤的敏感性。一个隐性作用基因座，充当乳腺的抑制剂肿瘤（SuprMAML）已映射到小鼠染色体的10 MB区域。相反，重组途径介导了trp53 inmammarytumors的杂合性丧失，并遗传为遗传为自然特征。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。这些观测提供了一种鉴定基因和途径的方法，并影响小鼠对乳腺肿瘤的敏感性。特定iaM 1：分析乳腺乳腺抑制作用的影响将检查肿瘤抑制基因。表达构造将被引入乳腺上皮细胞系和更换的intumor发病率将征收bemonitor。 AIM 1.2：DMBT1蛋白质ninormal人类的表达将确定乳腺组织和肿瘤以评估DMBT1作为生物标志物的价值。特定目的2：Suprmaml基因座对乳腺肿瘤发生率的遗传解剖。目的 2.1：Suprmaml基因座对乳腺肿瘤发生率的肿瘤抑制作用的大小将可以在先天小鼠中确定。 AIM 2.2：间隔将在单独的先天小鼠中细分以细化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。遗传背景可能会影响对乳房乳房乳腺癌的敏感性，从而通过了dnarepair的速率或保真度。因此，将使用合成底物监测DNA双链断裂修复的速率。识别型杀伤性tommammarytumors Will ProvideMarkers for Riskassessment 用于治疗干预的和novel目标。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Virus-inspired approach to nonviral gene delivery vehicles.

DOI：
10.1021/bm900370p
发表时间：
2009-08-10
期刊：
Biomacromolecules
影响因子：
6.2
作者：
Roy R;Jerry DJ;Thayumanavan S
通讯作者：
Thayumanavan S

Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice.

有助于 BALB/c-Trp53/- 小鼠自发性乳腺肿瘤发生的途径。

DOI：
10.2353/ajpath.2010.090438
发表时间：
2010
期刊：
The American journal of pathology
影响因子：
0
作者：
Yan,Haoheng;Blackburn,AnnekeC;McLary,SChristine;Tao,Luwei;Roberts,AmyL;Xavier,ElizabethA;Dickinson,EllenS;Seo,JaeHong;Arenas,RichardB;Otis,ChristopherN;Cao,QingJ;Lawlor,RebeccaG;Osborne,BarbaraA;Kittrell,FrancesS;Me
通讯作者：
Me

Regulation of cancer stem cells by p53.

p53 对癌症干细胞的调节。