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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.

项目概述：与其他癌症一样，卵巢癌被认为是通过一个多步骤的过程产生的，在这个过程中，克隆选择作用于具有体细胞突变和基因表达改变的细胞，从而使具有越来越强的生长特性的变异后代生长出来。癌症中突变的基因经常编码在保守信号通路中起作用的蛋白质。卵巢癌的一种亚型，即卵巢子宫内膜样腺癌（OEA），其特征是Wnt/¿-cat/Tcf信号通路的常见缺陷（即CTNNB1、APC、AXIN1或axin2基因的突变）。我们已经表明，该途径的状态是oea中全局基因表达的主要决定因素。通过比较通路完整和通路失调肿瘤中的基因表达，我们发现了几个¿-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K-Ras的激活和Pten的失活导致与人类oea相似的组织病理特征的癌。但是，在PI3K/Pten/Akt通路缺陷的人类oea中，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。具体来说，具有Wnt/¿-cat/Tcf通路缺陷的人类oea通常含有解除PI3K/Pten/Akt信号调控的突变。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努力，包括开发和分析OEA小鼠模型的工作，该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OEA发病机制中重要的¿-cat/Tcf调控基因；2)完成oea中已知调控PI3K/Pten/Akt信号通路的编码蛋白基因的全面突变分析，确定与该信号通路缺陷相关的基因表达特征；3)定义和表征OEA发病机制中与PI3K/Pten/Akt信号失调相关的关键下游转录靶基因；4)继续研究OEA小鼠模型，包括一种基于卵巢表面上皮Wnt/¿-cat/Tcf和PI3K/Pten/Akt信号条条性失调的新模型。相关性：我们的研究将增强我们对一种特定类型卵巢癌的分子基础的理解，并将使我们能够开发和表征卵巢癌的小鼠模型，这可能是测试针对特定细胞信号通路的新疗法的最大实用工具。