Mouse Model of Endometrial Tumorigenesis

描述(申请人提供)：子宫内膜癌是最常见的女性生殖道恶性肿瘤，是美国女性癌症相关死亡的第八大常见原因。子宫内膜癌大致分为两大类，即I型和II型。I型肿瘤是最常见的子宫内膜癌类型，约占所有病例的85%。相比之下，II型肿瘤是高级别的侵袭性肿瘤，患有这种疾病的女性在出现这种疾病时往往有转移。尽管他们的发病率很低，但他们的攻击性行为导致了不成比例的子宫内膜癌死亡人数，五年存活率仅为10%-30%。UEC中最常见的分子遗传学改变是PTEN抑癌基因和PIK3CA癌基因的突变。虽然这两个基因的蛋白产物的主要功能是调节PI3K/AKT/PTEN通路，该通路是控制细胞增殖和生长的关键途径，但我们最近发现PTEN突变在CAH和UEC中存在，而PIK3CA突变主要限于UEC。此外，雌激素及其在子宫内膜中的主要受体ER通过激活PI3K/AKT/PTEN通路刺激子宫内膜的增殖。II型肿瘤的形态原型是子宫浆液性癌(USC)，这是一种主要发生在绝经后妇女的高级别肿瘤。它最常发生在绝经后缺乏雌激素引起的子宫内膜萎缩的背景下。已经确定了一种前驱病变，称为子宫内膜上皮内癌(EIC)。它由形态上与USC相同的细胞组成，局限于上皮表面，没有可识别的侵袭。由于肿瘤的侵袭性，EIC或USC的妇女对子宫内膜进行采样，进行全腹子宫切除术和完全分期。目前，还没有有效的筛查方法来检测早期疾病。而且，像UEC一样，辅助治疗不会改变患有USC的女性的长期存活率。这一应用的主要假设是PTEN和PIK3CA突变导致PI3K/AKT/PTEN通路的失控以及雌激素/雌激素受体的异常是子宫内膜癌发生的中心。拟议中的一系列实验，使用基于基因的小鼠模型和人类原发肿瘤，将确定最常见的基因改变的作用及其与激素在子宫内膜癌发展中的关系。这些研究将增加我们对这种疾病的基本了解，为诊断提供新的生物标志物，并为未来开发这种常见疾病的新治疗方法创造动物模型。公共卫生相关性：子宫内膜癌是女性生殖道最常见的恶性肿瘤，在美国导致显著的死亡率和发病率。这项申请中提议的实验将产生新的诊断工具，并创建忠实地模仿人类疾病的遗传小鼠模型，可用于开发这种常见癌症的新疗法。

DESCRIPTION (provided by applicant): Endometrial cancer is the most frequent malignancy of the female genital tract and the eighth most common cause of cancer-related deaths of women in the United States. Endometrial carcinoma is broadly categorized into two major types, referred to as Type I and Type II. Type I tumors are the most common type of endometrial carcinoma and account for approximately 85% of cases. In contrast, Type II tumors are high-grade, aggressive tumors and women with this disease often have metastases at the time of presentation. Despite their low incidence, their aggressive behavior results in a disproportionate number of deaths due to endometrial carcinoma, with a five-year survival of only 10-30%. The most common molecular genetic alterations in UEC are mutations of the PTEN tumor suppressor gene and the PIK3CA oncogene. Although the main function of the protein products of both genes is regulation of the PI3K/AKT/PTEN pathway, a key pathway in controlling many aspects of cell proliferation and cell growth, we have recently shown that mutations in PTEN are present in CAH and UEC, whereas PIK3CA mutations are largely confined to UEC. Furthermore, estrogen and its primary receptor in the endometrium, ER, stimulate endometrial proliferation via activation of the PI3K/AKT/PTEN pathway. The morphologic prototype of Type II tumors is uterine serous carcinoma (USC) a high-grade tumor that occurs largely in postmenopausal women. It most commonly arises in the background of endometrial atrophy due to a lack of estrogen in the postmenopausal setting. A precursor lesion has been identified, called endometrial intraepithelial carcinoma (EIC). It consists of cells morphologically identical to those of USC, that are confined to the epithelial surfaces, without identifiable invasion. Due to the aggressive nature of the tumor, women with EIC or USC on endometrial sampling, undergo total abdominal hysterectomy and complete staging. Currently, there are no effective screening modalities for detecting early stage disease. And, like for UEC, adjuvant therapy does not change the long-term survival of women with USC. The overarching hypothesis of this application is that deregulation of PI3K/AKT/PTEN pathway by PTEN and PIK3CA mutations and estrogen/ER abnormalities are central to the development of endometrial carcinoma. The proposed set of experiments, using genetically based mouse models and primary human tumors, will define the role of the most common genetic alterations and their relationship to hormones on the development of endometrial carcinoma. These studies will increase our basic understanding of the disease, provide novel biomarkers for diagnosis, and create animal models for the future development of novel therapeutic approaches to this common disease. PUBLIC HEALTH RELEVANCE: Endometrial carcinoma, the most common malignancy of the female genital tract, causes significant mortality and morbidity in the United States. The experiments proposed in this application will result in novel diagnostic tools and create genetic mouse models that faithfully emulate the human disease that can be used to develop novel treatments for this common cancer.