Molecular Pathogenesis of Ovarian Endometrioid Adenocarcinomas

卵巢子宫内膜样腺癌的分子发病机制

基本信息

批准号：
7625101
负责人：
KATHLEEN R. CHO
金额：
$ 26.12万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7625101
关键词：
AXIN1 gene AXIN2 gene Address Adenocarcinoma Cell Behavior Binding CTNNB1 gene Cancer Biology Cancer Etiology Carcinoma Cell Cycle Progression Cell Fate Control Cell Survival Cell physiology Cells Clear Cell Clinical Data Defect Development Disease Doctor of Medicine Epithelial Epithelium Family Felis catus Gene Expression Gene Expression Profile Gene Mutation Gene Targeting Genes Growth Human Knowledge Learning Link Malignant Neoplasms Malignant neoplasm of ovary Modeling Molecular Molecular Genetics Morbidity - disease rate Mucinous Mus Mutate Mutation Nutrient Ovarian Ovarian Carcinoma Ovarian Endometrioid Adenocarcinoma Pathogenesis Pathway interactions Play Pongidae Process Property Proteins Research Personnel Role Serous Signal Pathway Signal Transduction Signal Transduction Inhibitor Somatic Mutation Surface Testing Therapeutic Variant Woman Work angiogenesis base cancer cell cancer therapy cell motility genetic analysis mortality mouse model new therapeutic target pre-clinical programs protein function receptor response trait tumor

项目摘要

DESCRIPTION (provided by applicant): Project Summary: Like other cancers, ovarian carcinomas are thought to arise through a multi-step process in which clonal selection acts on cells with somatic mutations and altered gene expression to allow outgrowth of variant progeny with increasingly aggressive growth properties. The genes mutated in cancer frequently encode proteins that function in conserved signaling pathways. One subtype of ovarian carcinoma, namely ovarian endometrioid adenocarcinoma (OEA), is characterized by frequent defects in the Wnt/¿-cat/Tcf signaling pathway (i.e., mutations in the CTNNB1, APC, AXIN1 orAXIN2 genes). We have shown the status of this pathway is a major determinant of global gene expression in OEAs. Through comparison of gene expression in pathway-intact versus pathway-deregulated tumors, we have identified several ¿ -cat/Tcf activated genes likely to play important roles in OEA pathogenesis. Activation of K-Ras and inactivation of Pten in the ovarian surface epithelium of mice leads to carcinomas with histopathologic features similar to human OEAs. But, in human OEAs with PI3K/Pten/Akt pathway defects, K-Ras mutations are not often seen. We have now acquired data suggesting Wnt/ ¿ -cat/Tcf and PI3K/Pten/Akt signaling pathway defects likely cooperate in OEA pathogenesis. Specifically, human OEAs with Wnt/ ¿ -cat/Tcf pathway defects often harbor mutations that deregulate PI3K/Pten/Akt signaling. This application describes efforts to define the molecular mechanisms by which defects in these two pathways contribute to the pathogenesis and clinical behavior of OEAs, including work to develop and analyze murine models of OEA that recapitulate the signaling pathway defects observed in human tumors. Toward this end, four aims are proposed: 1) To continue efforts to identify and characterize ¿-cat/Tcf regulated genes important in OEA pathogenesis; 2) To complete a comprehensive mutational analysis of genes encoding proteins known to regulate PI3K/Pten/Akt signaling in OEAs, and to define a gene expression signature associated with defects in this signaling pathway; 3) To define and characterize key downstream transcriptional target genes linked to deregulated PI3K/Pten/Akt signaling in OEA pathogenesis; and 4) To continue efforts to characterize mouse models of OEA, including a new model based on conditional deregulation of Wnt/ ¿-cat/Tcf and PI3K/Pten/Akt signaling in the ovarian surface epithelium. Relevance: Our studies will enhance our understanding of the molecular basis underlying a particular type of ovarian cancer, and will allow us to develop and characterize mouse models of ovarian cancer likely to be of greatest utility for testing novel therapeutics that target specific cell signaling pathways.

描述（由申请人提供）：项目摘要：与其他癌症一样，卵巢癌被认为是通过一个多步骤过程产生的，其中克隆选择作用于具有体细胞突变和基因表达的细胞，以允许生长出具有越来越侵袭性生长特性的变异子代。癌症中突变的基因经常编码在保守信号通路中发挥作用的蛋白质，即卵巢子宫内膜样腺癌（OEA），其特征是卵巢癌中经常出现缺陷。 Wnt/¿ -cat/Tcf 信号通路（即 CTNNB1、APC、AXIN1 或 AXIN2 基因中的突变）通过比较完整通路和通路中的基因表达，我们发现该通路的状态是 OEA 中全局基因表达的主要决定因素。途径失调的肿瘤，我们已经确定了几种 ¿ -cat/Tcf 激活的基因可能在 OEA 发病机制中发挥重要作用小鼠卵巢表面上皮中 K-Ras 的激活和 Pten 的失活导致具有与人类 OEA 相似的组织病理学特征的癌症，但是，在具有 PI3K/ 的人类 OEA 中。 Pten/Akt 通路缺陷、K-Ras 突变并不常见，我们现在获得的数据表明 Wnt/¿ -cat/Tcf 和 PI3K/Pten/Akt 信号通路缺陷可能在 OEA 发病机制中协同作用，特别是，具有 Wnt/¿ -cat/Tcf 通路缺陷通常含有使 PI3K/Pten/Akt 信号传导失调的突变。本申请描述了定义这两种通路缺陷导致 OEA 发病机制和临床行为的分子机制的工作，包括开发和分析工作。 OEA 小鼠模型概括了在人类肿瘤中观察到的信号通路缺陷，为此，提出了四个目标：1）继续努力识别和表征 ¿ -cat/Tcf 调节 OEA 发病机制中重要的基因；2) 完成对已知调节 OEA 中 PI3K/Pten/Akt 信号传导的基因蛋白的全面突变分析，并定义与该信号传导途径缺陷相关的基因表达特征； 3) 定义和表征与 OEA 发病机制中 PI3K/Pten/Akt 信号失调相关的关键下游转录靶基因；以及 4) 继续努力表征 OEA 小鼠模型，包括一种新的小鼠模型；基于 Wnt/ ¿ 条件放松管制的模型- 卵巢表面上皮细胞中的 cat/Tcf 和 PI3K/Pten/Akt 信号传导相关性：我们的研究将增强我们对特定类型卵巢癌分子基础的理解，并使我们能够开发和表征卵巢癌小鼠模型。可能对于测试针对特定细胞信号传导途径的新疗法最有用。