p27 as a Predictor of Endometrial Cancer Risk
B Djordjevic, A McCampbell, J Burzawa, K Lu, R Broaddus. MD Anderson Cancer Center, Houston, TX
Background: p27 is a nuclear protein that inhibits cell cycle progression and is controlled by insulin and adiponectin receptor signaling through the AKT signaling pathway. Activation of the adiponectin receptors 1 and 2 (AR1 and AR2) leads to inhibition of AKT and maintains p27–mediated cell cycle control. On the other hand, insulin-like growth factor 1 receptor (IGF 1R) is up-regulated in endometrial carcinomas and is thought to drive proliferation by activating AKT, which in turn targets p27 for degradation. We have shown in endometrial cancers that p27 either has decreased nuclear expression or changes its localization to the cytoplasm. The goal of this study was to assess p27 expression as potential biomarker of endometrial cancer risk in obese women, a group at risk for endometrial cancer.
Design: 51 timed endometrial biopsies were collected on days 5-10 of the menstrual cycle from asymptomatic lean (BMI<30; n=10) and obese (BMI>30; n=41) women. Presence of proliferative-phase endometrium was histologically verified. p27 immunohistochemistry (IHC) was scored semi-quantitatively. QPCR was used to asses levels of AR1, AR2 and IGF 1R. Statistical comparisons were performed by ANOVA with significance defined as p<0.05.
Results: There were four distinct categories of nuclear p27 expression depending on the number of glands with p27 expression and the number of cells per gland with p27 expression. Cytoplasmic staining for p27 did not correlate with loss of nuclear staining. In the lean women, there was a statistically significant correlation between decreasing AR1 and AR2 and decreasing p27. In the obese women, absolute levels of AR1 and AR2 were similar to those of lean women with decreased p27. The obese women showed a statistically significant correlation between increasing IGF 1R and decreasing p27 levels. Absolute IGR 1R levels were dramatically increased compared to the lean group. Importantly, the lowest p27 expression category was not identified in the lean group, but was present in 19% of cases in the obese group.
Conclusions: Abnormalities in adiponectin and insulin receptor signaling networks are present in proliferative-phase endometrium of asymptomatic obese women. Their combined effect results in inappropriately low p27 levels and potentially compromised cell cycle regulation. As such, p27 may represent a better marker of endometrial cancer risk than BMI alone and thus may assist in triaging asymptomatic obese women for increased endometrial cancer surveillance.
Category: Gynecologic & Obstetrics
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 130, Wednesday Morning