Mouse Model of Endometrial Tumorigenesis

描述（由申请人提供）：我们实验室的长期目标是开发一种生物学相关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。子宫内膜异位症是由增生的子宫内膜引起的，在无对抗性雌激素的情况下，通过一系列称为增生的组织病理学前体病变。UEC的直接前体，复杂型非典型增生（CAH），除了缺乏间质浸润外，与UEC非常相似。由于无法预测哪些前驱病变可能进展，以及在子宫内膜取样时区分CAH和UEC的形态学模糊，许多妇女因良性、非侵入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肿瘤发生发展中的作用，将对子宫内膜增生性病变的诊断和治疗产生重大影响。UEC中最常见的两种分子遗传异常是PTEN肿瘤抑制基因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了PTEN突变和MI，这表明这两种改变都发生在UEC发病机制的相对早期。最近，据报道，CAH在100%的雌性Pten小鼠中发展，并且在40周龄时在大约20%的小鼠中发展为癌。在本提案中，我们将通过以下具体目标进一步开发和利用该模型：1.目的：应用Affyrin寡核苷酸芯片筛选Pten/Mlh 1-/-小鼠非侵袭性和侵袭性子宫内膜病变的差异表达基因。2.为了确定在小鼠模型中发现的复杂非典型增生和类胶质瘤中差异表达的所选候选基因是否是人类侵袭性疾病的有用标志物（目的1）。3.应用光镜、免疫组化和分子生物学技术研究外源性雌孕激素化合物对Pten小鼠子宫内膜肿瘤发生的影响。4.评价雌激素受体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.