Mouse Model of Endometrial Tumorigenesis

描述(申请人提供)：我们实验室的长期目标是开发一种具有生物学意义的子宫内膜癌小鼠模型，以解决临床上重要的问题。子宫内膜癌是美国女性生殖道最常见的恶性肿瘤，子宫内膜样癌(UEC)是最常见的亚型。UEC起源于增殖的子宫内膜，在非对立雌激素的作用下，通过一系列称为增生性病变的组织病理学前驱病变。UEC的直接前体是复杂性不典型增生(CAH)，除了它没有间质侵袭外，它与UEC非常相似。由于无法预测哪些先兆病变可能进展，以及在子宫内膜采样中区分CAH和UEC的形态模糊，许多妇女因良性、非侵袭性疾病而接受子宫切除术。因此，更深入地了解CAH和UEC之间的差异，以及激素和遗传因素在子宫内膜癌发生发展中的作用，将对女性增生性子宫内膜病变的诊断和治疗产生重大影响。目前在UEC中发现的两种最常见的分子遗传学异常是PTEN抑癌基因的突变和微卫星不稳定性(MI)，分别存在于30-50%和20%的肿瘤中。在CAH的一个亚组中也检测到PTEN突变和MI，这表明这两种变化在UEC的发病机制中都相对较早发生。最近有报道称，100%的雌性Pten小鼠发生CAH，约20%的小鼠在40周龄时进展为肿瘤。在本方案中，我们将通过以下具体目标进一步开发和利用这一模型：1.利用Affymetrix寡核苷酸芯片鉴定非侵袭性和侵袭性子宫内膜病变之间的差异表达基因。2.确定在小鼠复杂不典型增生和子宫内膜样癌模型(AIM 1)中发现差异表达的候选基因是否为人类侵袭性疾病的有用标志物。3.应用光镜、免疫组织化学和分子生物学技术，探讨外源性雌激素和孕激素化合物对Pten小鼠子宫内膜肿瘤形成的影响。4.探讨雌激素受体α在Pten+/-小鼠子宫内膜肿瘤发生中的作用。

DESCRIPTION (provided by applicant): The long-term goal of our laboratory is to develop a biologically relevant mouse model of endometrial carcinoma for the purpose of addressing clinically important questions. Endometrial carcinoma is the most common malignancy of the female genital tract in the United States, and uterine endometrioid carcinoma (UEC) is the most prevalent subtype. UEC arises from proliferative endometrium, in the setting of unopposed estrogen, via a continuum of histopathological precursor lesions called hyperplasias. The direct precursor of UEC, complex atypical hyperplasia (CAH), closely resembles UEC with the exception that it lacks stromal invasion. Because of the inability to predict which precursor lesions may progress and the morphologic ambiguities of distinguishing between CAH and UEC on endometrial sampling, numerous women undergo hysterectomy for benign, non-invasive disease. Thus, a more thorough understanding of the differences between CAH and UEC, and the role of both hormonal and genetic factors on the development and progression of endometrial tumorigenesis would have a substantial impact on the diagnosis and management of women with proliferative endometrial lesions. The two most common molecular genetic abnormalities yet identified in UEC are mutations in the PTEN tumor suppressor gene and microsatellite instability (MI) which are present in 30-50% and 20% of tumors, respectively. PTEN mutations and MI have also been detected in a subset of CAH suggesting that both alterations occur relatively early in the pathogenesis of UEC. Recently it has been reported that CAH develops in 100% of female Pten mice and progresses to carcinoma in approximately 20% of mice at 40 weeks of age. In this proposal we will further develop and exploit this model through the following specific aims: 1. To identify differentially expressed genes between non-invasive and invasive endometrial lesions in Pten/Mlh1-/- mice with Affymetrix oligonucleotides microarrays. 2. To ascertain if selected candidate genes found to be differentially expressed in complex atypical hyperplasia and endometrioid carcinoma in the mouse model (Aim 1) are useful markers of invasive disease in humans. 3. To determine the effect of exogenous estrogen and progestational compounds on endometrial tumorigenesis in Pten mice using light microscopy, immunohistochemistry and molecular techniques. 4. To evaluate the role of the estrogen receptor alpha on endometrial tumorigenesis in Pten +/- mice.