Obesity-driven endometrial hyperplasia in postmenopausal women: Synergistic role for insulin and estrone

项目总结/摘要 肥胖导致的癌症有很好的描述，据报道，子宫内膜癌的风险最高。 流行病学研究表明，子宫内膜腺癌（EC）随着肥胖严重程度的增加， 增加，超重、中度、重度和极重度肥胖的相对风险分别为1.5、2.5、4.5和7.1， 分别随着肥胖症的流行，EC的发病率也在上升。EC有前驱病变，非典型子宫内膜 增生（AEH）。虽然AEH具有30%的高转化率，但AEH生长缓慢， 预防的机会。然而，我们不知道为什么肥胖促进AEH和EC的发展。 本项目旨在研究肥胖导致子宫内膜异位症的两种途径， 绝经后妇女的增生。我们假设病理生理水平的雌酮促进 不规则的腺体结构，而高胰岛素血症在一个协同过程中促进核内分泌， 导致子宫内膜非典型增生在这个项目中，我们将描述子宫内膜组织学的变化 和子宫基因表达，随着时间的推移发生，在小鼠谁具有病理生理水平的胰岛素， 雌酮，如发生在肥胖妇女。对于激素诱导组织学的确证性试验，我们将使用 建立了雌激素受体α（ERα）和胰岛素受体（IR）缺失小鼠模型。我们还将 检查胰岛素和雌酮联合刺激对小鼠的组织学影响。成果包括 对AEH的组织学和基因表达变化的时间轴评估。最后，我们提出一个案例- 对照研究，以阐明胰岛素和雌酮是否在绝经后AEH的发展中发挥作用 妇女我们打算招募30名患有AEH的女性和30名没有AEH的女性，她们都有严重的肥胖。 将测量循环雌酮和胰岛素水平，并评估子宫内膜组织的IR和ERα 表达水平以及全局基因表达。我们将确定胰岛素和雌酮的基因模式， 通过比较AEH和良性子宫内膜之间的差异基因表达， 来自胰岛素和/或雌酮暴露小鼠的子宫相对于其对照的差异基因表达。的 这项研究的直接影响可能包括开放AEH的临床管理， 已确立的减肥策略，用于治疗2型糖尿病的降胰岛素药物，以及 用于治疗乳腺癌的雌酮降低剂。这一事件的长期、广泛影响 研究的目的是了解肥胖引起的代谢和激素变化如何改变 易患许多肥胖导致的癌症。

PROJECT SUMMARY / ABSTRACT Obesity-driven cancers are well described, and the highest risk is reported for endometrial cancer. Epidemiological studies show an impressive escalation in endometrial adenocarcinoma (EC) as obesity severity increases, with relative risks of 1.5, 2.5, 4.5 and 7.1 for overweight, moderate, severe and very severe obesity, respectively. Rates of EC are rising with the obesity epidemic. EC has a precursor lesion, atypical endometrial hyperplasia (AEH). While AEH has a high transformation rate of 30% to EC, AEH grows slowly, offering the opportunity for prevention. However, we do not know why obesity promotes the development of AEH and EC. This project proposes to investigate two pathways for the development of obesity-driven endometrial hyperplasia in post-menopausal women. We hypothesize that pathophysiological levels of estrone promote irregular gland architecture, whereas hyperinsulinemia promotes nuclear atypia in a synergistic process that leads to atypical endometrial hyperplasia. In this project we will characterize changes in endometrial histology and uterine gene expression that occur over time, in mice who have pathophysiological levels of insulin and estrone, as occur in women with obesity. For confirmatory testing of hormone induced histology, we will use established mouse models of estrogen receptor-α (ERα) and insulin receptor (IR) deletions. We will also examine the histological effect of combined insulin and estrone stimulation in mice. Outcomes include a timeline assessment of histological and gene expression changes toward AEH. Finally, we propose a case- control study to elucidate whether insulin and estrone play a role in AEH development in post-menopausal women. We intend to enroll 30 women with AEH and 30 women without AEH, who have severe obesity. Circulating estrone and insulin levels will be measured, and endometrial tissue will be assessed for IR and ERα expression levels as well as global gene expression. We will identify insulin and estrone patterns of gene expression in AEH by comparing differential gene expression between AEH and benign endometrium to differential gene expression of uteri from insulin &/or estrone exposed mice relative to their controls. The immediate implications of this research may include opening the clinical management of AEH to the well- established strategy of weight loss, insulin-lowering agents as used in the treatment of type 2 diabetes, and estrone lowering agents as used in the treatment of breast cancer. The longer-term, broader implications of this research are to understand the mechanisms for how obesity induced metabolic and hormone changes alter susceptibility to many obesity-driven cancers.