Abstract A13: Overexpression of adipokine receptors and dysregulation of AMPK signaling in normal and hyperplastic endometrium from obese women
Authors: McCampbell Adrienne S. , Burzawa Jennifer K. , Lu Karen H. , Zhang Qian , Walker Cheryl L. , Broaddus Russell R. 
Published: May 2012

Background: Excess adipose tissue in the obese woman produces inflammatory cytokines, called adipokines, that are thought to regulate proliferation in peripheral tissues such as the endometrium to promote the development of cancer. Epidemiological studies indicate that the adipokines IL-6, leptin, TNFα and adiponectin are dysregulated in the obese woman and in women with endometrial cancer (EC). Activation of the IGF-IR/PI3K/mTOR pathway is an important contributor to the development of endometrial complex atypical hyperplasia (CAH), the precursor to endometrioid-type endometrial cancer. Adipokines act through their receptors to activate pathways that exhibit signal transduction crosstalk with the IGF-IR/PI3K/mTOR pathway that is thought to either promote activation (IL-6, leptin) or inhibit this pathway (TNFα, adiponectin). The goal of these studies was to assess the corresponding adipokine receptors (IL-6Rα, IL6-Rβ, Ob-Rb, AdipoR1, AdipoR2, TNFαR1 and TNFαR2) expression and activation of AMPK and IGF-IR/PI3K/mTOR signaling pathways in normal endometrium from lean and obese women and in endometrial hyperplasia from obese women.

Methods: We quantitated adipokine receptor transcript levels of the receptors by qRT-PCR in timed endometrial biopsies obtained from lean women (BMI &lt; 25 kg/m2) and obese women (BMI &gt; 30 kg/m2) that were histologically confirmed to have normal proliferative phase endometrium. These biopsies were compared to biopsies from obese women with endometrial CAH. We assessed functional activation of AMPK and mTOR pathways by immunohistochemistry.

Results: There was a significant stepwise increase in the expression of AdipoR1, TNFαR1 and TNFαR2 in normal lean endometrium, normal obese endometrium and obese endometrial CAH. In addition, IL-6Rβ transcripts were significantly increased in obese endometrial CAH as compared to both lean and obese normal endometrium. Phosphorylation of AMPK was increased in obese normal endometrium compared to lean normal endometrium. Surprisingly, in endometrial CAH mTOR signaling was activated and activation of AMPK was lost compared to lean and obese normal endometrium.

Conclusions: The stepwise increase in the expression of AdipoR1, TNFαR1 and TNFαR2 in the obese endometrium and endometrial CAH as compared to normal lean endometrium suggests that dysregulation of adipokine receptor expression is an early event and may be predictive of women at risk of developing endometrial CAH and EC. The overexpression of AdipoR1 in obese endometrium may contribute to activation of AMPK. The overexpression of AdipoR1 and activation of AMPK in obese endometrium may be a compensatory mechanism to dampen growth factor signaling through the IGF-IR/PI3K/mTOR pathway. In endometrial CAH there is upregulation of IL-6Rβ which may contribute to activation of mTOR by activating PI3K upstream. Activation of mTOR and loss of AMPK activation may contribute to the abnormal proliferation seen in endometrial CAH. These studies suggest that overexpression of adipokine receptor expression may be an important contributor to the risk of endometrial hyperplasia and cancer in obese women.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A13.