Mouse Model of Endometrial Tumorigenesis

子宫内膜肿瘤发生的小鼠模型

• 批准号: 8259163
• 负责人: LORA Hedrick ELLENSON
• 金额: $ 32.06万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259163
• 关键词: Abdomen; Accounting; Address; Adjuvant Therapy; Aggressive behavior; Animal Model; Apoptosis; Appearance; Atrophic; Atypical hyperplasia; Biological Markers; Cancer Etiology; Carcinoma; Carcinoma in Situ; Categories; Cell Proliferation; Cells; Cessation of life; Complex; Development; Diagnosis; Diagnostic; Disease; Endometrial; Endometrial Carcinoma; Endometrioid Carcinoma; Endometrium; Epithelial; Epithelial Cells; Estrogen Receptor alpha; Estrogens; Event; Female; Future; Gene Expression Profiling; Genes; Genetic; Genital system; Gland; Hormones; Human; Hyperplasia; Hysterectomy; In Vitro; Incidence; Lesion; Malignant Neoplasms; Metastatic Carcinoma; Modality; Modeling; Molecular Genetics; Morbidity - disease rate; Mutation; Nature; Neoplasm Metastasis; Oncogenes; Operative Surgical Procedures; PI3K/AKT; PIK3CA gene; PTEN gene; Pathway interactions; Postmenopause; Procedures; Property; Prospective Studies; Regulation; Role; Sampling; Screening procedure; Serous; Staging; Surface; Time; Total Hysterectomy; Tumor Suppressor Genes; Type II Endometrial Adenocarcinoma; United States; Woman; base; cell growth; common treatment; effective therapy; human disease; human tissue; improved; in vivo; mortality; mouse model; novel; novel diagnostics; novel therapeutic intervention; protein function; prototype; receptor; research study; tool; tumor; tumorigenesis

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.

6。项目摘要 子宫内膜癌是女性生殖道最常见的恶性肿瘤，也是第八位的恶性肿瘤 在美国，妇女与癌症相关死亡的常见原因。子宫内膜癌为 大致分为两种主要类型，称为I型和II型。 I型肿瘤是 最常见的子宫内膜癌类型，约占病例的85％。在 对比，II型肿瘤是高级，侵略性肿瘤，患有这种疾病的女性通常具有 演示时转移。尽管发生率低，但他们的侵略性行为结果 由于子宫内膜癌导致的死亡人数不成比例，只有五年的生存率 10-30％。 UEC中最常见的分子遗传改变是PTEN肿瘤的突变 抑制基因和PIK3CA癌基因。虽然蛋白质产物的主要功能 这两个基因都是对PI3K/AKT/PTEN途径的调节，这是控制许多方面的关键途径 细胞增殖和细胞生长，我们最近表明，PTEN中存在突变 CAH和UEC，而PIK3CA突变主要局限于UEC。此外，雌激素和 它在子宫内膜中的主要受体通过激活刺激子宫内膜增殖 PI3K/AKT/PTEN途径。 II型肿瘤的形态原型是子宫浆液性癌 （USC）一种高级肿瘤，主要发生在绝经后妇女中。最常见的是 由于绝经后环境中缺乏雌激素，子宫内膜萎缩的背景。一个 已经鉴定出前体病变，称为子宫内膜上皮内癌（EIC）。它由 细胞在形态上与USC相同，而USC仅限于上皮表面，而没有 可识别的入侵。由于肿瘤的侵略性，具有EIC或USC的妇女在 子宫内膜采样，进行总腹部子宫切除术和完整分期。目前，那里 没有用于检测早期疾病的有效筛查方式。而且，就像UEC一样，佐剂 治疗不会改变USC妇女的长期生存。总体假设 该应用是通过PTEN和PIK3CA突变对PI3K/AKT/PTEN途径放松管制 雌激素/ER异常对于子宫内膜癌的发展至关重要。提议 使用基于遗传的小鼠模型和原发性人肿瘤的一组实验将定义 最常见的遗传改变的作用及其与激素的关系在发展中 子宫内膜癌。这些研究将增加我们对疾病的基本理解，提供 新颖的生物标志物用于诊断，并创建动物模型，为新颖的未来发展 这种常见疾病的治疗方法。