Androgen Receptor Expression in Endometrial Carcinoma

Abstract

Endometrial carcinoma (ECA) is frequently hormonally driven and can be treated with endocrine-based therapy, yet hormone receptor status is not routinely assessed. In particular, little is known about the significance of androgen receptor (AR) in ECA. Androgen has antiproliferative effects in the healthy endometrium and could serve a similar role to progesterone in curbing the progression of estrogen-dependent neoplasia. There may also be a subset of ECA that benefits from androgen antagonistic therapy. We herein investigate AR expression across ECA subtypes and compare its expression to estrogen receptor (ER) and progesterone receptor (PR). Immunohistochemical staining for AR, ER, and PR was performed on an endometrial tissue microarray containing 50 ECA with a variety of morphologic subtypes as well as 20 benign and 9 atypical hyperplastic endometria. AR was expressed by 54% (27/50) of ECA including 60% of low grade endometrioid carcinomas, 70% high grade endometrioid carcinomas, 70% serous carcinomas, 50% carcinosarcomas, and 20% clear cell carcinomas. High AR expression was chiefly restricted to a subset of serous carcinomas (50%). AR expression occurred most often in concert with ER staining, although 5 high grade cancers (1 serous carcinoma, 4 carcinosarcomas) showed AR expression in the absence of ER. In summary, AR positivity is seen in over half of ECA in our study, including the majority of low grade endometrioid carcinomas, high grade endometrioid carcinomas, and serous carcinomas. High level expression is seen in half of serous carcinomas and a subset of serous carcinomas and carcinosarcomas show some degree of AR staining in the absence of ER, suggesting a possible role for androgen inhibition in treatment of these cases.

Identification of a novel subgroup of endometrial cancer patients with loss of thyroid hormone receptor beta expression and improved survival

“…4). Three of these NHRsprogesterone receptor (PGR), estrogen receptor 1 (ESR1), and androgen receptor (AR)have been previously reported to lose expression in subsets of endometrial carcinomas [10,23], which confirms that our approach can capture NHRs known to lose expression in endometrial carcinoma. The proportion of tumors that lose expression for each gene varies widely, along with the shapes of the gene expression distribution.…”

“…The loss of estrogen, progesterone, and androgen receptor expression has been used to define clinically-relevant subtypes of endometrial tumors that are associated with poor outcomes [23,31,37]. Here, a novel open-source tool termed receptLoss was developed to identify subsets of patient tumors that have lost NHR expression relative to normal tissue.…”

Androgen receptor expression in endometrial carcinoma and its correlation with clinicopathologic features

“…In the prior studies most of the work focused on endometrioid EC, as it seems to arise as a result of hormonal drive. In a recent study, it was noted that 70% of serous cancers and 50% of carcinosarcoma also show AR expression and high levels of AR expression was noted in half of serous carcinoma [ 12 ]. These findings correlate with results of our study as we found 42.8% serous cancers to express AR, while high AR expression was also noted in serous carcinoma.…”

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma

“…Women with elevated circulating androgens have a 2-3 fold increased risk of developing endometrial cancer and administration of synthetic androgens to mice results in endometrial hyperplasia [2]. In humans, multiple studies observed increased AR protein expression in endometrial hyperplasia and cancer, with low-grade endometrioid, or type-I carcinomas more commonly positive than higher grade histologies [3][4][5][6]. Furthermore, positive AR expression has been associated with improved prognosis relative to AR-negative tumors [3,6].…”