Mouse Model of Endometrial Tumorigenesis

6.项目摘要 子宫内膜癌是女性生殖道最常见的恶性肿瘤， 是美国女性癌症相关死亡的常见原因。子宫内膜癌是 大致分为两大类，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 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 在出现时转移。尽管发病率很低，但他们的攻击行为导致 子宫内膜癌死亡人数不成比例，5年生存率仅为 10- 30% UEC中最常见的分子遗传学改变是PTEN肿瘤的突变 抑制基因和PIK 3CA癌基因。虽然蛋白质产品的主要功能 这两个基因都是PI 3 K/AKT/PTEN通路的调节基因，这是一个控制许多方面的关键通路， 细胞增殖和细胞生长，我们最近表明，在PTEN突变存在于细胞增殖和细胞生长， CAH和UEC，而PIK 3CA突变主要限于UEC。此外，雌激素和 其在子宫内膜中的主要受体ER通过激活 PI 3 K/AKT/PTEN通路。II型肿瘤的形态学原型是子宫浆液性癌 (USC)一种主要发生于绝经后妇女的高度恶性肿瘤。它最常出现在 绝经后由于缺乏雌激素导致子宫内膜萎缩的背景。一 已经确定了称为子宫内膜上皮内癌（EIC）的前驱病变。它包括 细胞形态与USC相同，局限于上皮表面， 可识别的入侵由于肿瘤的侵袭性，患有EIC或USC的女性 子宫内膜取样，进行腹式全子宫切除术并完成分期。目前 没有有效的筛查方法来检测早期疾病。和UEC一样， 治疗不会改变USC妇女的长期生存率。最重要的假设是 该应用是通过PTEN和PIK 3CA突变解除PI 3 K/AKT/PTEN途径的调节， 雌激素/ER异常是子宫内膜癌发生的中心环节。拟议 一组实验，使用基于遗传的小鼠模型和原发性人类肿瘤，将定义 最常见的遗传改变的作用及其与激素的关系， 子宫内膜癌这些研究将增加我们对这种疾病的基本了解， 新的诊断生物标志物，并为未来开发新的 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.