Mouse Model of Endometrial Tumorigenesis

子宫内膜肿瘤发生的小鼠模型

• 批准号: 6919930
• 负责人: LORA Hedrick ELLENSON
• 金额: $ 33.64万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919930
• 关键词: carcinogenesis; endometrium; estrogen receptors; estrogens; female; gene environment interaction; gene expression; gene mutation; genetic markers; genetic models; genetically modified animals; hormone regulation /control mechanism; hormone related neoplasm /cancer; human tissue; immunocytochemistry; laboratory mouse; microarray technology; model design /development; molecular genetics; neoplasm /cancer genetics; neoplastic process; nucleic acid repetitive sequence; sex hormones; tumor suppressor genes; uterus neoplasms; uterus preneoplastic state

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.

描述（由申请人提供）：我们实验室的长期目标是开发一种与生物学相关的子宫内膜癌模型，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，子宫子宫内膜癌（UEC）是最普遍的亚型。 UEC是由增生性子宫内膜引起的，在无毒性雌激素的情况下，通过称为增生的组织病理学前体病变的连续体。 UEC的直接前体是复杂的非典型增生（CAH），与UEC非常相似，但缺乏基质的侵袭。由于无法预测哪些前体病变可能会进展，并且可以区分子宫内膜采样的CAH和UEC的形态歧义，因此许多女性接受了良性，非侵入性疾病的子宫切除术。因此，对CAH和UEC之间的差异以及荷尔蒙和遗传因素在子宫内膜肿瘤发生的发展和进展中的作用更加详尽，将对具有增殖性子宫内膜病变的女性的诊断和管理产生重大影响。在UEC中鉴定出的两个最常见的分子遗传异常是PTEN肿瘤抑制基因和微卫星不稳定性（MI）的突变，分别存在于30-50％和20％的肿瘤中。在CAH的一部分中也检测到了PTEN突变和MI，这表明这两种改变在UEC的发病机理中相对早期发生。最近，据报道，CAH在100％的雌性PTEN小鼠中发展，并在40周龄大约20％的小鼠中发展为癌。在此提案中，我们将通过以下特定目的进一步开发和利用该模型：1。在PTEN/MLH1 - / - 小鼠中使用Affymetrix寡核苷酸微阵列中的PTEN/MLH1-/ - 小鼠中的非侵入性和浸润性子宫内膜病变之间的差异表达基因。 2。为了确定在小鼠模型中发现的选定候选基因是否在复杂的非典型增生和子宫内膜类药物癌中差异表达（AIM 1）是人类侵入性疾病的有用标记。 3。使用光学显微镜，免疫组织化学和分子技术来确定外源雌激素和孕激素化合物对PTEN小鼠子宫内膜肿瘤发生的影响。 4。评估雌激素受体α对PTEN +/-小鼠子宫内膜肿瘤发生的作用。