Wky Rat Genetic Model for Breast Cancer Susceptibility

Wky 大鼠乳腺癌易感性遗传模型

• 批准号: 8267017
• 负责人: MICHAEL N GOULD
• 金额: $ 30.97万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267017
• 关键词: Alkylating Agents; Alleles; Area; Biological; Biological Assay; Breast; Breast Carcinoma; Cancer Etiology; Carcinogens; Cells; ChIP-on-chip; Chromosomes; DNA; DNA Resequencing; Data; Disease; ERBB2 gene; Elements; Engineering; Enhancers; Epigenetic Process; Etiology; Functional RNA; Genes; Genetic; Genetic Models; Genomics; Gland; Goals; Health; Homologous Gene; Human; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Maps; Methods; Modeling; Molecular Conformation; Oncogenes; Organ; Pathway interactions; Phenotype; Predisposition; Progress Reports; Public Health; Quantitative Trait Loci; Rattus; Recombinants; Relative (related person); Risk Marker; Site; T-Lymphocyte; Testing; Transplantation; Woman; cancer risk; cell type; congenic; dimethylbenzanthracene; genetic element; genome wide association study; insight; malignant breast neoplasm; novel; prevent; promoter

DESCRIPTION (provided by applicant): Mcs5 is a mammary carcinoma susceptibility rat quantitative trait locus (QTL) that contains at least three sub-loci (Mcs5a, -5b, and -5c) which contribute to susceptibility and show epistatic interactions with one another. We have shown that Mcs5a, a non-mammary gland cell autonomous locus, is a compound QTL having two interacting elements which differentially control Fbxo10 in T cells. SNPs in human homologues of both of these two elements have each been shown to associate with breast cancer risk in women (n E 12,000). The goal of this continuation proposal is to further study the Mcs5 QTL by characterizing Mcs5c and Mcs5b. The first aim will focus on genetic and biological studies using existing congenic recombinant rat models for the Mcs5c and Mcs5b loci. Both loci will be fine mapped to intervals below 200 Kb. We will also determine if these loci act in a mammary cell autonomous manner. Next, the reduced genomic intervals of Mcs5b and Mcs5c will be annotated by comparing the WKy and WF alleles in order to identify well-defined candidate elements within these loci which underlie their susceptibility phenotypes. The genes and organ/cell type through which each locus exerts its effect on mammary cancer susceptibility will be determined. Focusing on the identified cell type, further genetic and epigenetic differences between the WKy and WF alleles at these two loci will be annotated. Examples of methods to be used include: ChIP-CHIP; chromosome conformation capture assay (3C); resequencing areas identified as potentially functional. Selected candidate loci for Mcs5c and Mcs5b will be validated by producing and characterizing appropriate genetically engineered rat models. This project will identify and characterize novel mammary cancer risk associated alleles. Preliminary data and previous results with Mcs5a suggest that human homologues of these alleles may also contribute to breast cancer risk in humans. Finally, functional studies of the Mcs5c and Mcs5b alleles will define unique pathways involved in the etiology of breast cancer. PUBLIC HEALTH RELEVANCE: This project is directly relative to public health in that it will investigate unique aspects of the genetic component of breast cancer etiology. It is also possible that it will provide risk markers for human breast cancer. Broadly, it will also likely provide new insights for interpretation of the results of genome-wide association studies for common diseases.

描述（由申请人提供）：Mcs5是一个乳腺癌易感性大鼠数量性状位点（QTL），包含至少三个亚位点（Mcs5a、-5b和-5c），它们与易感性有关，并表现出上位性相互作用。我们已经证明，Mcs5a，一个非乳腺细胞自主位点，是一个复合QTL，具有两个相互作用的元件，在T细胞中差异控制Fbxo10。这两种元素的人类同源物中的单核苷酸多态性已被证明与女性患乳腺癌的风险有关（n E 12,000）。本研究的目标是通过对Mcs5c和Mcs5b的表征来进一步研究mcs55 QTL。第一个目标将集中在利用现有的Mcs5c和Mcs5b基因座基因重组大鼠模型进行遗传和生物学研究。这两个位点都可以很好地映射到200 Kb以下的间隔。我们还将确定这些基因座是否以乳腺细胞自主的方式起作用。接下来，将通过比较WKy和WF等位基因来标注Mcs5b和Mcs5c的缩短的基因组间隔，以便在这些位点中确定明确的候选元件，这些元件是其易感表型的基础。将确定每个位点对乳腺癌易感性产生影响的基因和器官/细胞类型。以鉴定的细胞类型为重点，进一步说明WKy和WF等位基因在这两个位点上的遗传和表观遗传差异。可使用的方法示例包括：ChIP-CHIP；染色体构象捕获法（3C）；重新排序确定的潜在功能区域。选定的Mcs5c和Mcs5b候选位点将通过生产和表征适当的基因工程大鼠模型来验证。该项目将识别和表征新的乳腺癌风险相关等位基因。mc5a的初步数据和先前的结果表明，这些等位基因的人类同源物也可能与人类患乳腺癌的风险有关。最后，对Mcs5c和Mcs5b等位基因的功能研究将确定与乳腺癌病因有关的独特途径。公共卫生相关性：该项目与公共卫生直接相关，因为它将调查乳腺癌病因的遗传成分的独特方面。它也有可能为人类乳腺癌提供风险标记。从广义上讲，它也可能为解释常见疾病的全基因组关联研究结果提供新的见解。

项目成果

Precocious differentiation of the virgin Wistar-Kyoto rat mammary gland.

处女 Wistar-Kyoto 大鼠乳腺的早熟分化。

• DOI: 10.1210/endo.140.6.6626
• 发表时间: 1999
• 期刊: Endocrinology.
• 作者: Benton,ME;Chen,KS;Haag,JD;Sattler,CA;Gould,MN
• 通讯作者: Gould,MN

Mcs5c: a mammary carcinoma susceptibility locus located in a gene desert that associates with tenascin C expression.

Mcs5c：位于基因荒漠中的乳腺癌易感位点，与生腱蛋白 C 表达相关。

• DOI: 10.1158/1940-6207.capr-10-0187
• 发表时间: 2011
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Veillet,AdelineL;Haag,JillD;Remfert,JaneL;Meilahn,AmandaL;Samuelson,DavidJ;Gould,MichaelN
• 通讯作者: Gould,MichaelN

Effective flow cytometric phenotyping of cells using minimal amounts of antibody.

使用最少量的抗体对细胞进行有效的流式细胞术表型分析。

• DOI: 10.2144/0000113854
• 发表时间: 2012
• 期刊: BioTechniques
• 影响因子: 2.7
• 作者: Sharma,Deepak;Eichelberg,MarkR;Haag,JillD;Meilahn,AmandaL;Muelbl,MatthewJ;Schell,Kathy;Smits,BartMG;Gould,MichaelN
• 通讯作者: Gould,MichaelN

Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats.

• DOI: 10.1371/journal.pone.0026145
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sharma D;Smits BM;Eichelberg MR;Meilahn AL;Muelbl MJ;Haag JD;Gould MN
• 通讯作者: Gould MN

Physical evidence of Mcs5, a QTL controlling mammary carcinoma susceptibility, in congenic rats.

Mcs5（一种控制乳腺癌易感性的 QTL）在同系大鼠中的物理证据。

• DOI: 10.1093/carcin/bgg112
• 发表时间: 2003
• 期刊: Carcinogenesis.
• 作者: Samuelson,DavidJ;Haag,JillD;Lan,Hong;Monson,DinelliM;Shultz,MillicentA;Kolman,BradleyD;Gould,MichaelN
• 通讯作者: Gould,MichaelN