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-? (ER?) 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 ER? 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.

Public Health Relevance

Obesity is an independent risk factor for atypical endometrial hyperplasia, a precancerous condition of the uterus, but we do not know which attributes of obesity contribute to hyperplasia development. Since obesity is associated with high levels of insulin and estrone, we will investigate the role of these hormones as growth factors in hyperplasia development, by studying a mouse model and the genetic signature of human hyperplasia. Study results will give us a better understanding of how obesity promotes abnormal growth of the endometrium, and may provide evidence for the use of diabetes and obesity medications for the treatment of atypical endometrial hyperplasia.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Halvorson, Lisa M
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Yale University
Obstetrics & Gynecology
Schools of Medicine
New Haven
United States
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