Molecular Pathogenesis of Ovarian Endometrioid Adenocarcinomas

描述（由申请人提供）：项目概述：与其他癌症一样，卵巢癌被认为是通过多步骤过程产生的，其中克隆选择作用于具有体细胞突变和改变的基因表达的细胞，以允许具有越来越积极的生长特性的变异后代的生长。在癌症中突变的基因通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，即卵巢类囊腺癌（OEA），其特征在于Wnt/β-cat/Tcf信号通路中的频繁缺陷（即，CTNNB 1、APC、AXIN 1或AXIN 2基因中的突变）。我们已经表明，这一途径的状态是一个主要的决定因素，全球基因表达的OEAs。通过比较通路完整与通路失调肿瘤中的基因表达，我们已经确定了几个可能在OEA发病机制中发挥重要作用的<$cat/Tcf激活基因。小鼠卵巢表面上皮中K-Ras的激活和Pten的失活导致具有与人类OEAs相似的组织病理学特征的癌。但是，在PI 3 K/Pten/Akt通路缺陷的人OEAs中，K-Ras突变并不常见。我们现在已经获得的数据表明Wnt/<$-cat/Tcf和PI 3 K/Pten/Akt信号通路缺陷可能在OEA发病机制中协同作用。具体而言，具有Wnt/<$-cat/Tcf通路缺陷的人OEAs通常具有使PI 3 K/Pten/Akt信号转导失调的突变。本申请描述了定义这两种途径中的缺陷导致OEA的发病机制和临床行为的分子机制的努力，包括开发和分析OEA的小鼠模型的工作，该模型概括了在人类肿瘤中观察到的信号传导途径缺陷。为此，提出了四个目标：1）继续努力鉴定和表征OEA发病机制中重要的<$-cat/Tcf调节基因; 2）完成对已知调节OEA中PI 3 K/Pten/Akt信号传导的蛋白质编码基因的全面突变分析，并确定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PI 3 K/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，包括基于Wnt/Akt信号条件性失调的新模型。- 卵巢表面上皮中的cat/Tcf和PI 3 K/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，这些模型可能对测试靶向特定细胞信号通路的新型疗法具有最大的实用性。

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.