Androgen receptor as potential therapeutic target in metastatic endometrial cancer

Abstract

PurposeThe expression and involvement of estrogen (ER) and progesterone receptor (PR) is extensively studied in endometrial cancer. Androgen receptor (AR) is a hormone receptor less studied in female cancers, and we here aim to investigate the expression level of AR in endometrial cancer precursor lesions, primary tumors and metastases, and its potential as therapeutic target.ResultsExpression of AR was observed in 93% of hyperplasias, but only in 41% of non-endometrioid tumors. Compared to estrogen and progesterone receptor AR is more commonly expressed in metastatic lesions, and AR status is discordant in primary and metastatic lesions in a large proportion of cases. AR protein level was significantly associated with survival (P < 0.001), and a calculated AR to ERα ratio identified a subgroup of patients with particular poor outcome. The anti-androgen enzalutamide may have a growth inhibitory effect in endometrial cancer cells based on experiments with primary endometrial tumor cells.MATERIALS AND METHODS718 primary endometrial cancers and 298 metastatic lesions (from 142 patients) were investigated for expression of AR in relation to survival, clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array; mRNA levels by DNA oligonucleotide microarray. The effect of androgen stimulation and inhibition was tested on primary endometrial tumor cells.ConclusionsA large proportion of metastatic endometrial cancer lesions express AR, which may be a potential target in these patients. Treatment targeting AR may be of particular benefit in patients with high AR levels compared to ERα levels.

Blocking 17β‐hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

“…Local steroid metabolism and intracrinology offer opportunities for novel drug targets and prognosis markers in hormone-dependent conditions such as EC [15,22,[35][36][37][38][39]. At the same time, however, intracrine networks are complex; can convert adrenal steroid precursors into androgens and estrogens; and can interconvert androgens, estrogens, active and inactive compounds, and protective and cancer-promoting compounds.…”

“…$ In the case of more than one metastasis corresponding to one primary EC, the metastatic lesion with the higher 17β-HSD-1 mRNA level was considered. # The mRNA levels between the primary and metastasis were considered different when they deviated by more than ± 0.03 arbitrary mRNA units (± 0.5% of the mRNA value).^ERα expression was determined by immunohistochemistry as described previously [15].^^Five samples were classified as carcinosarcomas; three were clear cell ECs; and one sample was classified as undifferentiated EC.…”

Glucocorticoid receptor expression is associated with inferior overall survival independent of BRCA mutation status in ovarian cancer

“…A recent in-depth immunohistochemistry analysis demonstrated that high glucocorticoid receptor protein is associated with decreased time to progression in patients with epithelial ovarian cancer 1. High glucocorticoid receptor also correlates with decreased survival in estrogen receptor -negative breast cancer2 and endometrial cancer,3 suggesting glucocorticoid receptor expression and activity may have prognostic value in a variety of cancer types. In addition to its role in regulating gene expression critical to immunity in lymphocytes, glucocorticoid signaling has direct effects on epithelial tumor cells.…”

Blood steroid levels predict survival in endometrial cancer and reflect tumor estrogen signaling

“…Immunohistochemical staining and evaluation of hormone receptors has been performed previously for this cohort [14,[25][26][27]. Expression data for estrogen receptor (ERα), progesterone receptor (PR), Androgen Receptor (AR) and Glucocorticoid Receptor (GR) was available for 93, 94, 87 and 76 patients, respectively.…”