Androgen receptor as potential therapeutic target in metastatic endometrial cancer

• Published in: Oncotarget Vol. 7; no. 31; pp. 49289 - 49298
• Main Authors: Tangen, Ingvild Løberg, Onyango, Therese Bredholt, Kopperud, Reidun, Berg, Anna, Halle, Mari K, Øyan, Anne M, Werner, Henrica M J, Trovik, Jone, Kalland, Karl Henning, Salvesen, Helga B, Krakstad, Camilla
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 02.08.2016
• Subjects: Aged; Androgen Antagonists - therapeutic use; Endometrial Neoplasms - metabolism; Estrogen Receptor alpha - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Middle Aged; Neoplasm Metastasis; Phenotype; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Receptors, Androgen - metabolism; Receptors, Progesterone - metabolism; Research Paper; RNA, Messenger - metabolism; Tissue Array Analysis; Treatment Outcome; endometrial cancer; androgen receptor; biomarker; survival
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.10334

The 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. Expression 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. 718 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. A 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.