Mouse Model of Endometrial Tumorigenesis

子宫内膜肿瘤发生的小鼠模型

• 批准号: 7880705
• 负责人: LORA Hedrick ELLENSON
• 金额: $ 33.05万
• 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/7880705
• 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; PIK3CA gene; PTEN gene; Pathway interactions; Postmenopause; Procedures; Property; Prospective Studies; Regulation; Role; Sampling; Screening procedure; Serous; Staging; Surface; TP53 gene; 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; public health relevance; receptor; research study; tool; tumor; tumorigenesis

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.

描述（由申请人提供）：子宫内膜癌是女性生殖道最常见的恶性肿瘤，也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%。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有转移。尽管其发病率低，但其侵略性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肿瘤抑制基因和PIK 3CA癌基因的突变。虽然这两种基因的蛋白产物的主要功能是调节PI 3 K/AKT/PTEN途径，这是控制细胞增殖和细胞生长的许多方面的关键途径，但我们最近表明，PTEN突变存在于CAH和UEC中，而PIK 3CA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PI 3 K/AKT/PTEN途径刺激子宫内膜增殖。II型肿瘤的形态学原型是子宫浆液性癌（USC），这是一种高级别肿瘤，主要发生在绝经后妇女中。它最常见于绝经后由于缺乏雌激素而引起的子宫内膜萎缩。子宫内膜上皮内癌（EIC）是一种早期病变。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子宫内膜取样的妇女，进行全腹子宫切除术和完整的分期。目前，没有有效的筛查模式来检测早期疾病。而且，与UEC一样，辅助治疗不会改变USC女性的长期生存率。本申请的首要假设是，由PTEN和PIK 3CA突变引起的PI 3 K/AKT/PTEN途径的失调和雌激素/ER异常是子宫内膜癌发展的中心。使用基于遗传的小鼠模型和原发性人类肿瘤，拟议的一组实验将确定最常见的遗传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，提供新的诊断生物标志物，并为未来开发这种常见疾病的新治疗方法创造动物模型。公共卫生关系：子宫内膜癌是女性生殖道最常见的恶性肿瘤，在美国引起显著的死亡率和发病率。本申请中提出的实验将产生新的诊断工具，并创建遗传小鼠模型，忠实地模仿人类疾病，可用于开发这种常见癌症的新疗法。