Mouse Model of Diet-Enduced Endometrial Cancer

饮食诱发子宫内膜癌的小鼠模型

• 批准号: 9086305
• 负责人: Jill Slack-Davis
• 金额: $ 7.9万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086305
• 关键词: Accounting; Adult; Age; Alleles; Biological Models; Bladder; Consumption; Data; Defect; Development; Diagnosis; Diet; Dietary Factors; Dietary Intervention; Dietary intake; Disease; Distant Metastasis; Endometrial; Endometrial Carcinoma; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Epidemic; Epidemiologic Studies; Epithelial; Epithelium; Exons; Experimental Animal Model; Fatty acid glycerol esters; Female; Female of child bearing age; Future; Glucose Intolerance; Goals; Gonadal Steroid Hormones; Growth; Health; Hormonal; Human; Incidence; Inflammation; Insulin Resistance; Intervention; Investigation; Kinetics; Link; Liver; LoxP-flanked allele; Lung; Malignant Neoplasms; Mediating; Metabolic; Modeling; Molecular; Mus; Myometrial; Neoplasm Metastasis; Obesity; PTEN gene; Pathway interactions; Physiology; Pilot Projects; Predisposition; Regulation; Reporting; Risk; Risk Factors; Role; STK11 gene; System; Testing; Tetracyclines; Time; Transgenic Mice; Tumor Suppressor Proteins; Uterus; Vagina; Woman; actionable mutation; age effect; cancer initiation; clinically relevant; design; feeding; insulin sensitivity; lymph nodes; mouse model; obesity treatment; obesogenic; parity; prevent; promoter; recombinase; reproductive tract; sugar; therapeutic target; tool; tumor; tumor progression; western diet

 DESCRIPTION (provided by applicant): Endometrial cancer is the most common malignancy in the female reproductive tract and accounts for 6% of all cancer in women. Obesity is a well-known risk factor for endometrial cancer such that up to 40% of endometrial cancer is attributed to excess adiposity, and morbidly obese women have a 6-fold increased risk of dying from this disease. The link between obesity and endometrial cancer is poorly understood, but risk factors include insulin resistance, glucose intolerance, low-grade inflammation, and elevated sex hormones. In addition, recent epidemiologic studies identified a link between increased dietary intake of sugar and endometrial cancer. Most of the studies linking obesity and sugar to endometrial cancer are correlative. A major barrier to defining the precise mechanisms whereby obesity and sugar drive endometrial cancer is the lack of an experimental animal model where endometrial cancer can be induced by feeding an obesigenic diet. The overarching goal of this pilot project is to generate and characterize the first diet-induced mouse models of endometrial cancer. We observe that deletion of one allele of the tumor suppressor LKB1 in the mouse endometrium confers diet-sensitive susceptibility to endometrial cancer. Herein, we will investigate the contribution of 2 different tumor suppressors associated with endometrial cancer development in humans, LKB1 and PTEN, by deleting each individually in the mouse epithelial endometrium using Cre-lox mediated deletion. We will test 2 different systems to delete floxed LKB1 or PTEN exons in the endometrial epithelium using transgenic mice that express Cre under the control of either the Sprr2f or Pax8 promoters. We hypothesize that consumption of a high fat/high sugar (Western) diet will accelerate endometrial tumor formation and progression in mice lacking one or both copies of the tumor suppressors LKB1 or PTEN in the endometrial epithelium. This hypothesis will be tested in two Specific Aims. Aim 1 will fully characterize the incidence and kinetics of endometrial cancer and potential metastatic progression in mice with heterozygous deletion of LKB1 achieved by Sprr2f-dependent expression of Cre. Aim 2 will employ a tetracycline-inducible Pax8- Cre system to delete LKB1 or PTEN in adult mice and evaluate the incidence and kinetics of tumor development in mice fed diets containing high fat or low fat. At a minimum, we expect to produce at least one model of endometrial cancer that is responsive to diet. This model would fill a significant void in the field and enable additional investigation of the role of specific dietary factors as well as molecular mechanisms in the regulation of endometrial cancer. The ability to manipulate the timing of LKB1 or PTEN loss (with inducible Pax8-Cre expression) in the context of Western diet feeding would facilitate future studies examining the effects of age, parity, and hormonal status in obesity-related endometrial 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，占女性所有癌症的 6%。肥胖是众所周知的子宫内膜癌危险因素，高达 40% 的子宫内膜癌归因于过度肥胖，病态肥胖女性死于这种疾病的风险增加 6 倍。肥胖与子宫内膜癌之间的联系尚不清楚，但危险因素包括胰岛素抵抗、葡萄糖不耐受、低度炎症和性激素升高。此外，最近的流行病学研究发现饮食中糖摄入量增加与子宫内膜癌之间存在联系。大多数将肥胖和糖与子宫内膜癌联系起来的研究都是相关的。定义肥胖和糖驱动子宫内膜癌的精确机制的一个主要障碍是缺乏可以通过喂养致肥胖饮食诱发子宫内膜癌的实验动物模型。该试点项目的总体目标是生成并表征第一个饮食诱导的子宫内膜癌小鼠模型。我们观察到，小鼠子宫内膜中肿瘤抑制因子 LKB1 的一个等位基因的缺失会导致对子宫内膜癌的饮食敏感易感性。在此，我们将通过使用 Cre-lox 介导的删除在小鼠上皮子宫内膜中单独删除每种抑制剂，来研究与人类子宫内膜癌发展相关的 2 种不同肿瘤抑制因子 LKB1 和 PTEN 的作用。我们将使用在 Sprr2f 或 Pax8 启动子控制下表达 Cre 的转基因小鼠测试 2 个不同的系统，以删除子宫内膜上皮中 floxed LKB1 或 PTEN 外显子。我们假设，在子宫内膜上皮细胞中缺乏肿瘤抑制因子 LKB1 或 PTEN 的一个或两个拷贝的小鼠中，食用高脂肪/高糖（西方）饮食会加速子宫内膜肿瘤的形成和进展。该假设将在两个具体目标中得到检验。目标 1 将全面表征子宫内膜癌的发病率和动力学，以及通过 Sprr2f 依赖的 Cre 表达实现 LKB1 杂合缺失的小鼠中潜在的转移进展。目标 2 将采用四环素诱导型 Pax8-Cre 系统来删除成年小鼠中的 LKB1 或 PTEN，并评估饲喂高脂肪或低脂肪饮食的小鼠中肿瘤发展的发生率和动力学。至少，我们期望产生至少一种对饮食有反应的子宫内膜癌模型。该模型将填补该领域的重大空白，并能够进一步研究特定饮食因素的作用以及子宫内膜癌调节中的分子机制。在西方饮食喂养的背景下操纵 LKB1 或 PTEN 丢失（具有诱导型 Pax8-Cre 表达）时间的能力将有助于未来研究年龄、产次和激素状态对肥胖相关子宫内膜癌的影响。