Abstract 947: Effect of estrogen on gene expression profiling in endometrium of obese, insulin resistant animals
Authors: Zhang Qian , Celestino Joseph , Zhang Jiexin , Loose David , Lu Karen H. 
Published: February 2011

Abstract
Introduction: Epidemiologic studies have demonstrated that obese women have a 2-3.5-fold increased risk for endometrial cancer. In an animal model of obesity and insulin resistance, we previously showed that estrogen enhances obese rat endometrial cell proliferation through induction of pro-proliferative gene expression and suppression of anti-proliferative genes. The purpose of the current study is to find new markers that are associated with the pronounced estrogen effect in obese, insulin resistant rat endometrium.
Methods: Using ovariectomized Zucker Fa/Fa obese rats and lean control, we compared estrogen induced signaling with cDNA micro-array analysis between obese and lean rat endometrium. RT-qPCR analysis was used to validate micro-array data. For one novel gene, cgrrf1, expression was examined in normal human endometrium and hyperplasia tissue.
Results: Micro-array analysis demonstrated that 3040 gene responded to estrogen treatment in lean rat endometrium, while 3291 gene showed response in obese rats. Among them 1927 gene expression were changed in both lean and obese rat. 470 genes expression had pronounced alteration in obese rats than the lean one. These genes included a wide variety of signal pathway like metabolism signaling, acute response signaling, cell cycle, G1/S check point regulation signaling, PI3K/AKT signaling, G-protein coupled receptor signaling and Wnt β-catenin signaling. RT-qPCR analysis of gene c-fos and EIG121 expression validated micro-array data, and expression of c-Myc and cyclin A from our previous study also confirmed the micro-array data. Tumor suppressor gene cgrrf1 is one of the genes demonstrating pronounced estrogen effect in obese, insulin resistant rat endometrium: micro-array data showed estrogen treatment significantly decreased cgrrf1 expression in obese rats endometrium (p&lt;0.001), while in lean rats no change was noticed; qPCR data also showed that estrogen had a differential effect on cgrrf1 expression. The inhibiting effect was stronger in obese rats compared with lean rats (decreased 83.3% in obese vs. 68% in lean rats, p&lt;0.05). cgrrf1 expression was significantly lower in hyperplasia compared to normal human endometrium (p&lt;0.001). Insulin sensitizer metformin treatment significantly increased cgrrf1 expression in obese rats (p&lt;0.05), while in lean rats no metformin effect was observed.
Conclusion: Micro-array data identified differential gene expression between lean and obese, insulin resistant endometrium. cgrrf1 is a new marker whose expression was down regulated by estrogen treatment in obese, insulin resistant rat endometrium. In human hyperplasia tissue, cgrrf1 expression is significantly down regulated.
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 947.