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Characterization of Emca4, the Rat Ortholog of the 8q24 Breast Cancer Risk Locus

Emca4（8q24 乳腺癌风险基因座的大鼠直系同源物）的表征

基本信息

批准号：
9311738
负责人：
JAMES D SHULL
金额：
$ 41.86万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311738
关键词：
8q24 Alleles Alternative Splicing Animals Attention Biological Process Biology Breast CRISPR/Cas technology Cancer Etiology Candidate Disease Gene Cells Chromosomes Chromosomes, Human, Pair 7 Data Development Endocrine Epidemiology Estradiol Estrogens Etiology Exons Foundations Gene Expression Genes Genetic Genetic Determinism Genotype Goals Homeostasis Human Human Chromosomes Human Genome Individual Knowledge Laboratories Link Machine Learning Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Maps MicroRNAs Modeling Modification Molecular Oncoproteins Orthologous Gene PVT1 gene Patients Physiological Play Population Predisposition Prevention Public Health Quantitative Trait Loci Rat Strains Rattus Reagent Regulatory Element Research Resistance Risk Role Single Nucleotide Polymorphism Site Susceptibility Gene Testing Transcript Translating Untranslated RNA Variant base cancer risk cancer subtypes case control cell type chromosome conformation capture cohort experimental study gene product genetic risk factor genetic variant insight malignant breast neoplasm molecular phenotype neoplastic novel novel strategies predictive modeling promoter rat genome risk variant transcription factor transcriptome sequencing

项目摘要

Project Summary The ultimate goal of this research is to define the mechanisms through which specific endocrine and genetic risk factors contribute to breast cancer development. The focus of this proposed study is Emca4, a genetic determinant of susceptibility to 17β-estradiol (E2)-induced mammary cancer in the rat that has been mapped to rat chromosome 7 (RNO7). Data presented herein indicate that Emca4 harbors multiple genetic determinants of mammary cancer susceptibility that are orthologous to breast cancer risk loci mapped to chromosome 8q24.21. Also presented are novel data that indicate that a risk prediction model based on genotype across the Emca4 orthologous regions in the human genome can accurately distinguish cases from controls in a previously characterized case/control cohort. The primary objectives of this proposed study are to identify the cell types in which and the mechanisms through which the Emca4 variants influence development of mammary cancer. The knowledge gained will be translate to studies of human derived biospecimens to assess relevance of the data emerging from the rat models. Aim 1 is to define the mechanisms through which Emca4.1 determines susceptibility to E2-induced mammary cancer. The genes upon which the Emca4.1 variants act will be identified in defined mammary cell populations. Aim 2 is to define the mechanism through which Emca4.4 influences mammary cancer susceptibility and modifies the actions of Emca4.1. The molecular bases of the epistatic interactions between Emca4.4 and Emca4.1 on mammary cancer susceptibility and the cellular and molecular phenotypes regulated by Emca4.4 and Emca4.1 will be defined. Specific Aim 3 is to define the function(s) of Pvt1 in the rat mammary gland and its role in mammary cancer development. Attention will be focused on functionally characterizing Pvt1 promoters and exons that are impacted by endocrine and genetic factors or differ between matched normal and neoplastic mammary/breast tissues. Novel, physiologically relevant, rat models of E2-induced mammary cancer will be utilized in this research. Successful completion of the proposed studies proposed is expected to identify the cell types in which the actions of the Emca4 variants on mammary cancer susceptibility are exerted, the specific gene product(s) that confers the actions of the Emca4 variants in those cell types, and the downstream biological processes that are influenced by the functional orthologs that reside within Emca4. The information generated in these studies is expected to advance our understanding of the etiology of the luminal breast cancer subtypes.

项目总结