PTEN and the Molecular Genetics of Endometrial Cancer

描述（申请人提供）：子宫内膜癌（EC）在妇科恶性肿瘤中发病率排名第一，死亡率排名第二。最常见的子宫内膜癌是子宫内膜样腺癌，由子宫内膜增生发展而来。虽然已经确定了一些分子改变，但对子宫内膜癌的分子发病机制仍然知之甚少。子宫内膜癌的临床进展需要发展与人类疾病平行的动物模型。PTEN被鉴定为10q23染色体上的候选肿瘤抑制基因，该基因组区域在大量肿瘤中缺失。超过50%的子宫内膜样亚型的人类子宫内膜癌在PTEN位点存在突变或缺失。我们假设PTEN失活本身在子宫内膜癌发病的早期阶段起着关键作用，并在肿瘤进展中与其他遗传改变合作。我们建议通过直接体内遗传方法和以下策略来验证这一假设，并进一步表征PTEN抑制子宫内膜肿瘤发生的分子途径：在基因敲除小鼠中，确定PTEN在子宫内膜癌发生和发展中的作用。PTEN小鼠出现子宫内膜复合体非典型增生（CAH），这种病变被认为是EC的前兆。我们将阐明这些小鼠子宫内膜癌发病机制的分子机制，以及PTEN的完全缺失是否是子宫内膜肿瘤发生的先决条件。目标2。探讨PTEN小鼠子宫内膜癌发病的多步骤过程。我们将明确这些小鼠中协同性肿瘤发生的分子机制。我们将确定PTEN单倍体功能不全和/或PTEN缺失是否在子宫内膜癌发病过程中与癌基因的转化能力合作，或者在缺乏参与子宫内膜癌发病的肿瘤生长抑制基因的小鼠中，PTEN缺失是否会增加肿瘤发病率。目标3。目的：通过条件性PTEN失活制备子宫内膜癌小鼠模型。我们将通过Cre-loxP介导的方法完全灭活子宫内膜上皮中的PTEN。这些小鼠将与其他突变体杂交，以组织特异性的方式研究子宫内膜肿瘤发生的体内机制。

DESCRIPTION (provided by applicant): Endometrial cancer (EC) ranks first in incidence and second in mortality among gynecological malignancies. The most common type of endometrial cancer, endometrioid adenocarcinoma, develops from endometrial hyperplasia. Although several molecular alterations have been identified, the molecular pathogenesis of endometrial cancer remains poorly understood. Clinical advances on endometrial cancer require the development of animal models paralleling the human disease. PTEN was identified as a candidate tumor-suppressor gene on chromosome 10q23, a genomic region deleted in a large number of tumors. More than 50% of human endometrial cancers of the endometrioid subtype harbor mutations or deletions in the PTEN locus. We hypothesize that PTEN inactivation per se plays a critical role in the early phases of endometrial cancer pathogenesis and that it cooperates with other genetic alterations in tumor progression. We propose to test this hypothesis and further characterize the molecular pathways by which PTEN suppresses endometrial tumorigenesis through a direct in vivo genetic approach and the following strategy: Aim 1. To define, in knockout mice the role of PTEN in endometrial cancer initiation and progression. PTEN mice develop endometrial complex atypical hyperplasia (CAH), a lesion that is considered the precursor of EC. We will elucidate the molecular mechanisms underlying endometrial cancer pathogenesis in these mice and whether the complete loss of PTEN is a prerequisite for endometrial tumorigenesis. Aim 2. To dissect in the PTEN mouse the multistep process towards endometrial cancer pathogenesis. We will define the molecular mechanisms underlying cooperative oncogenesis in these mice. We will determine whether PTEN haploinsufficiency and/or PTEN loss cooperate in endometrial cancer pathogenesis with the transforming ability of oncogenes, or whether it increases tumor incidence in mice lacking tumor-growth suppressor genes involved in endometrial cancer pathogenesis. Aim 3. To generate a mouse model of endometrial cancer by conditional PTEN inactivation. We will completely inactivate PTEN in the endometrial epithelium by a Cre-loxP mediated approach. These mice will be intercrossed with other mutants to study in vivo the mechanisms of endometrial tumorigenesis in a tissue specific manner.