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

绝经后妇女肥胖导致的子宫内膜增生：胰岛素和雌酮的协同作用

• 批准号: 10593167
• 负责人: Clare Ann Flannery
• 金额: $ 42.04万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593167
• 关键词: Age; Architecture; Atypical Endometrial Hyperplasias; Benign; Body Weight decreased; Body mass index; Breast Cancer Treatment; Case/Control Studies; Chronic; Clinical Management; Data; Development; Diabetes Mellitus; Endometrial; Endometrial Carcinoma; Endometrial Hyperplasia; Endometrial adenocarcinoma; Endometrium; Enrollment; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Estrone; Frequencies; GPER gene; Gene Expression; Gene Expression Profile; Genomics; Gland; Growth; Growth Factor; Histologic; Histology; Hormones; Human; Hyperinsulinism; Hyperplasia; Inflammation; Insulin; Insulin Receptor; Insulin Signaling Pathway; Knock-out; Lesion; Ligands; Malignant Neoplasms; Measures; Mediating; Menopause; Metabolic; Metabolic hormone; Modeling; Morbid Obesity; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Atypia; Obesity; Obesity Epidemic; Outcome; Ovarian; Ovary; Overweight; Pathway interactions; Pattern; Pharmaceutical Preparations; Placebos; Postmenopause; Precancerous Conditions; Predisposition; Prevention; Process; Production; Progesterone; Progestins; Proliferating; Protein Isoforms; Receptor Signaling; Regulation; Relative Risks; Reporting; Research; Risk Factors; Role; Severities; Stimulation of Cell Proliferation; Testing; Thinness; Time; Tissue-Specific Gene Expression; Tissues; Transgenic Organisms; Uterus; Wild Type Mouse; Withdrawal; Woman; Work; aged; clinical phenotype; epidemiology study; genetic signature; high risk; insulin signaling; mouse model; obesity development; receptor; synergism; timeline; transcriptome

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.

项目摘要 /摘要 肥胖驱动的癌症得到了很好的描述，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）的令人印象深刻的升级 增加，相对风险为1.5、2.5、4.5和7.1，超重，中度，严重和非常严重的肥胖症 肥胖流行的EC发生率正在上升。 EC具有前体病变，非典型子宫内膜 增生（aeh）。虽然AEH对EC的高转化率为30％，但AEH的增长缓慢，提供了 预防机会。但是，我们不知道为什么肥胖会促进AEH和EC的发展。 该项目的提议要研究肥胖驱动子宫内膜开发的两种途径 绝经后妇女的增生。我们假设雌狮的病理生理水平促进 不规则的腺体结构，而高胰岛素血症在协同过程中促进核亚型 导致非典型子宫内膜增生。在这个项目中，我们将表征子宫内膜组织学的变化 在具有病理生理水平的胰岛素和病理生理水平和 埃斯特隆，肥胖女性发生。为了确认马龙诱导的组织学，我们将使用 建立的雌激素受体-α（ERα）和胰岛素受体（IR）缺失的小鼠模型。我们也会 检查小鼠胰岛素和雌激素刺激的组合组织学效应。结果包括 组织学和基因表达的时间轴评估对AEH的变化。最后，我们提出了一个案件 - 控制研究以阐明胰岛素和雌酮在绝经后的AEH发育中发挥作用 女性。我们打算将30名患有AEH的妇女和30名没有AEH的妇女招募，这些妇女患有严重的肥胖症。 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 表达水平以及全球基因表达。我们将确定基因的胰岛素和雌激素模式 通过比较AEH和良性子宫内膜之间的差异基因表达与AEH的表达 胰岛素和/或雌酮暴露的小鼠的子宫表达相对于其对照。这 这项研究的直接影响可能包括将AEH的临床管理开放给 在治疗2型糖尿病的治疗和 雌酮降低药物用于治疗乳腺癌。长期，更广泛的含义 研究将了解肥胖诱导的代谢和马酮的变化的机制 对许多肥胖驱动癌症的敏感性。