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

项目摘要 这项研究的最终目标是确定特定的内分泌和遗传风险 乳腺癌的发生与多种因素有关。这项拟议研究的重点是Emca4，一种遗传性 17β-雌二醇(E2)诱导的大鼠乳腺癌易感性的决定因素已被定位到 大鼠7号染色体(RNO7)。这里提供的数据表明，Emca4含有多种基因决定因素 定位于染色体8q24.21的乳腺癌易感基因与乳腺癌易感基因相关。 还提供了新的数据，表明基于Emca4基因的风险预测模型 人类基因组中的同源区域可以准确地区分病例和对照 特色化病例/对照队列。这项拟议的研究的主要目标是确定 Emca4基因变异对乳腺癌发生的影响及其机制。这个 所获得的知识将转化为对人类衍生生物标本的研究，以评估数据的相关性 从老鼠模型中浮现出来。目标1是定义Emca4.1决定的机制 对雌激素诱导的乳腺癌的易感性。Emca4.1变异体作用的基因将被确定 在特定的乳腺细胞群中。目标2是定义Emca4.4影响的机制 乳腺癌易感性和修饰Emca4.1的作用。上位性的分子基础 Emca4.4和Emca4.1在乳腺癌易感性及细胞和分子水平上的相互作用 将定义由Emca4.4和Emca4.1调节的表型。具体目标3是定义(S)的功能 大鼠乳腺中的PVT1及其在乳腺癌发生中的作用。我们将把注意力集中在 受内分泌和遗传因素影响或不同的PVT1启动子和外显子的功能特征 在配对的正常和肿瘤乳腺/乳腺组织之间。新的、生理上相关的大鼠模型 这项研究将利用雌二醇诱导的乳腺癌。圆满完成拟议的研究 预计将确定Emca4变体在乳腺癌中的作用所在的细胞类型 易感性发挥，特定的基因产物(S)，赋予Emca4变体在这些 细胞类型，以及受驻留的功能同源基因影响的下游生物过程 在Emca4内部。这些研究所产生的资料可望加深我们对 管腔乳腺癌亚型的病因学研究。

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.