Abstract 2929: Adipokine receptor dysregulation and AMPK signaling in histologically normal endometrium from obese women and in endometrial tumorigenesis

Abstract

Abstract Background: Obesity is a significant risk factor for the development of endometrial cancer (EC). Endometrial tissue biomarkers of risk would be useful in identifying obese women at particular risk for developing EC. Excess adipose tissue produces inflammatory cytokines, called adipokines that are thought to regulate proliferation in the endometrium and promote the development of EC. Epidemiological studies indicate that the adipokines adiponectin, leptin, IL-6 and TNFα are dysregulated in the obese woman and in women with EC. Activation of the mTOR pathway is an important contributor to the development of endometrial complex atypical hyperplasia (CAH), the precursor to EC. In normal metabolic tissues, adipokines act through their receptors to activate pathways including AMPK that crosstalk with the mTOR pathway to either promote activation (leptin, IL-6) or cause inhibition (adiponectin, TNFα). The goal of these studies was to assess adipokine receptor (AdipoR1, AdipoR2, Ob-Rb, IL-6Rα, IL6-Rβ TNFαR1 and TNFαR2) expression and activation of AMPK and mTOR signaling in histologically normal endometrium from lean and obese women and in endometrial CAH and EC. Methods: We quantitated adipokine receptor transcript levels by qRT-PCR in timed endometrial biopsies obtained from lean women (BMI < 25.0kg/m2) and obese women (BMI > 30.0kg/m2) that were histologically confirmed to have normal proliferative phase endometrium. These biopsies were compared to biopsies from obese women with CAH and EC. We assessed functional activation of AMPK (phosphorylation of T172 of AMPKα) and mTOR (phosphorylation of S235 of S6 ribosomal protein) pathways by immunohistochemistry. Results: There was a significant stepwise increase in the expression of AdipoR1, TNFαR1 and TNFαR2 in normal obese endometrium and endometrial CAH as compared to normal lean endometrium. The increased expression of AdipoR1, TNFαR1 and TNFαR2 seen in obese endometrium and CAH was not seen in EC. We identified increased expression of the Ob-Rb in EC as compared to normal endometrium and CAH. Surprisingly, AMPKα phosphorylation was increased in the normal obese endometrium compared to normal lean endometrium. AMPK phosphorylation was absent in the majority of CAH which showed activation of mTOR signaling. However, in the majority of EC with activated mTOR, AMPK was activated. Conclusions: Under conditions of obesity and tumorigenesis we identified up-regulation of receptors known in metabolic tissues to signal to AMPK. However, in the setting of tumorigenesis of the endometrium we identified upregulation of mTOR suggesting that there is a defect in the ability of AMPK to engage TSC2 and inhibit mTOR. These studies suggest that there may be a defect in AMPK regulation of mTOR signaling in obese women at risk for this disease. In addition, adipokine receptor expression may be a good biomarker of EC risk in obese women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2929.