Steroid receptor coactivator AIB1 in endometrial carcinoma, hyperplasia and normal endometrium: correlation with clinicopathologic parameters and biomarkers

Abstract

Members of the p160 steroid receptor cofactor family, including AIB1 (Amplified in Breast Cancer 1) (also known as SRC-3/RAC3/ACTR/pCIP/TRAM-1), are of interest in endometrial carcinoma as they affect the function of estrogen (ER) and progesterone receptors (PR). Since it is feasible that alterations in the expression levels of coregulators can either augment ER activity or reduce the ability of PR to oppose ER action in endometrial cancers, our primary aim was to analyze expression of the AIB1 protein in endometrial carcinoma, carcinoma-associated complex atypical hyperplasia, and carcinoma-associated normal endometrium using immunohistochemistry and tissue microarrays. Expression of AIB1 was compared with other biomarkers and clinicopathologic parameters. We also tested AIB1 expression in non-carcinoma associated hyperplastic, normal secretory and proliferative endometrium to determine baseline AIB1 levels. In endometrial carcinoma, there is a higher expression of AIB1 compared to carcinoma-associated complex atypical hyperplasia (0.007) or carcinoma-associated normal endometrium (<0.001). AIB1 expression correlates with older age (P=0.003), peri- or postmenopausal status (P=0.002) and a higher grade of carcinomas (P=0.04). There were no differences in the expression of additional steroid hormone receptor co-activators (SRC-1 and p300/CBP) and the co-repressor SMRT between histologic categories. AIB1 expression correlated with ER (r=0.30, P=0.006). The strongest correlation was between ER and PR-B isoform nuclear expression (r=0.52, P<0.0001). AIB1 levels were higher in non-carcinoma associated normal and hyperplastic endometrium compared to carcinoma-associated complex atypical hyperplasia and carcinoma-associated normal endometrium, and were the highest in normal secretory endometrium. In conclusion, high AIB1 expression in endometrial carcinoma is associated with parameters of poor prognosis. We propose that when AIB1 is overexpressed in endometrial carcinoma, ER action is augmented, leading to endometrial hyperplasia and progression to malignancy. Future studies correlating expression with response to hormonal therapy may be beneficial.