Mouse Model of Endometrial Tumorigenesis

6.项目总结 子宫内膜癌是女性生殖道最常见的恶性肿瘤，居第八位。 美国女性癌症相关死亡的常见原因。子宫内膜癌是 大致分为两种主要类型，称为I型和II型。I型肿瘤是 子宫内膜癌是最常见的类型，约占病例的85%。在……里面 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通常 表现时的转移。尽管他们的发生率很低，但他们的攻击性行为导致 死于子宫内膜癌的人数不成比例，五年存活率仅为 10%-30%。UEC中最常见的分子遗传学改变是PTEN肿瘤的突变 抑癌基因和PIK3CA癌基因。虽然蛋白产品的主要功能是 这两个基因都是PI3K/AKT/PTEN通路的调节者，PI3K/AKT/PTEN通路是控制许多方面的关键途径 在细胞增殖和细胞生长方面，我们最近发现PTEN的突变存在于 而PIK3CA突变主要局限于UEC。此外，雌激素和 它在子宫内膜的主要受体，ER，通过激活子宫内膜上的 PI3K/AKT/PTEN通路。II型肿瘤的形态原型是子宫浆液性癌 (南加州大学)一种主要发生在绝经后妇女的高级别肿瘤。它最常出现在 绝经后缺乏雌激素引起的子宫内膜萎缩的背景。一个 前驱病变已被发现，称为子宫内膜上皮内癌(EIC)。它由以下内容组成 细胞形态与USC相同，局限于上皮表面，没有 可识别的入侵。由于肿瘤的侵袭性，患有EIC或USC的女性 取子宫内膜标本，行开腹全子宫切除术和完全分期。目前，有 没有有效的筛查方法来检测早期疾病。和UEC一样，佐剂 治疗不会改变南加州大学女性的长期存活率。最重要的假设是 这一应用是通过PTEN和PIK3CA突变来解除对PI3K/AKT/PTEN通路的调控。 雌激素/雌激素受体异常是子宫内膜癌发生发展的中心环节。建议数 使用基于基因的小鼠模型和人类原发肿瘤的一系列实验将定义 最常见的基因改变及其与荷尔蒙的关系在糖尿病发生发展中的作用 子宫内膜癌。这些研究将增加我们对这种疾病的基本了解，提供 新的生物标志物用于诊断，并为未来的新的发展创造动物模型 治疗这种常见疾病的方法。

6. Project Summary 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.