Mouse Model of Diet-Enduced 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%。肥胖是子宫内膜癌的一个众所周知的危险因素，高达40%的子宫内膜癌归因于过度肥胖，病态肥胖的妇女死于这种疾病的风险增加了6倍。肥胖和子宫内膜癌之间的联系知之甚少，但风险因素包括胰岛素抵抗，葡萄糖耐受不良，轻度炎症和性激素升高。此外，最近的流行病学研究确定了糖的饮食摄入量增加与子宫内膜癌之间的联系。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通过喂养肥胖饮食诱导子宫内膜癌的实验动物模型。该试点项目的首要目标是产生和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基因LKB 1的一个等位基因的缺失赋予了子宫内膜癌的饮食敏感性。在此，我们将通过使用Cre-lox介导的缺失在小鼠上皮子宫内膜中分别缺失与人类子宫内膜癌发展相关的2种不同肿瘤抑制因子LKB 1和PTEN来研究其贡献。我们将使用在Sprr 2f或Pax 8启动子控制下表达Cre的转基因小鼠，测试2种不同的系统来删除子宫内膜上皮中的floxed LKB 1或PTEN外显子。我们假设，高脂肪/高糖（西方）饮食的消费将加速子宫内膜肿瘤的形成和发展的小鼠缺乏一个或两个副本的肿瘤抑制因子LKB 1或PTEN在子宫内膜上皮。这一假设将在两个具体目标中得到检验。目的1将充分表征子宫内膜癌的发病率和动力学以及通过Sprr 2f依赖性Cre表达实现的LKB 1杂合缺失的小鼠中的潜在转移进展。目的2将使用四环素诱导的Pax 8- Cre系统来删除成年小鼠中的LKB 1或PTEN，并评估喂食含有高脂肪或低脂肪的饮食的小鼠中肿瘤发展的发生率和动力学。至少，我们希望至少产生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一个重要空白，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控的分子机制。在西方饮食喂养的背景下，操纵LKB 1或PTEN丢失（具有诱导性Pax 8-Cre表达）的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。

 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.