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的机制， 导致乳腺癌的因素。这项研究的重点是Emca 4，一种遗传性的 大鼠对17β-雌二醇（E2）诱导的乳腺癌易感性的决定因素， 大鼠7号染色体（RNO 7）。本文提供的数据表明，Emca 4具有多个遗传决定因子， 乳腺癌易感性与定位于染色体8q24.21的乳腺癌风险基因座正相关。 还提供了新的数据，表明基于Emca基因型的风险预测模型4 人类基因组中的邻位区可以准确地区分病例和对照， 特征病例/对照队列。这项研究的主要目的是确定细胞类型， 以及Emca 4变异体影响乳腺癌发展的机制。的 将获得的知识转化为人源性生物标本的研究，以评估数据的相关性 从大鼠模型中出现。目标1是定义Emca4.1确定 易患E2诱导的乳腺癌。将鉴定Emca4.1变体作用的基因 在特定的乳腺细胞群中。目的2是定义Emca4.4影响的机制 乳腺癌易感性和修改的行动Emca4.1。上位性的分子基础 Emca4.4和Emca4.1对乳腺癌易感性的相互作用及其细胞和分子机制 将定义由Emca4.4和Emca4.1调节的表型。具体目标3是确定以下方面的职能： 大鼠乳腺中pvt 1的表达及其在乳腺癌发生中的作用。注意力将集中在 功能上表征Pvt 1启动子和外显子受内分泌和遗传因素影响或不同 在匹配的正常和肿瘤性乳腺/乳腺组织之间。新型生理学相关大鼠模型 E2诱导的乳腺癌将用于本研究。成功完成拟议的研究 预计提出的方法将确定Emca 4变体对乳腺癌作用的细胞类型。 易感性的发挥，特定的基因产物，赋予的行动，Emca 4变异体在这些 细胞类型和下游生物学过程，这些生物学过程受到存在于细胞中的功能性直向同源物的影响。 在Emca 4中。这些研究中产生的信息有望促进我们对 管腔型乳腺癌亚型的病因学。

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.