Androgen receptor as potential therapeutic target in metastatic endometrial cancer

Ingvild Løberg Tangen, Therese Bredholt Onyango, Reidun Kopperud, Anna Berg, Mari K Halle, Anne M Øyan, Henrica M J Werner, Jone Trovik, Karl Henning Kalland, Helga B Salvesen, Camilla Krakstad, Ingvild Løberg Tangen, Therese Bredholt Onyango, Reidun Kopperud, Anna Berg, Mari K Halle, Anne M Øyan, Henrica M J Werner, Jone Trovik, Karl Henning Kalland, Helga B Salvesen, Camilla Krakstad

Abstract

Purpose: 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.

Results: 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.

Materials and methods: 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.

Conclusions: 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.

Keywords: androgen receptor; biomarker; endometrial cancer; survival.

Conflict of interest statement

No potential conflicts of interest was disclosed.

Figures

Figure 1. AR expression decreases with dedifferentiation
Figure 1. AR expression decreases with dedifferentiation
AR expression in glandular cells was scored, with strong AR immunohistochemical staining shown in (A) and AR loss in (B). Both AR protein level (C) and mRNA (D) level decreased with dedifferentiation. Abbreviations: AR: androgen receptor, Gr: grade, NE: non-endometrioid, PT: primary tumor, Met: metastases, *Information on grade missing for 10 patients included in the study (7 AR positive and 3 AR negative)
Figure 2
Figure 2
Expression of the individual hormone receptors AR, PR and ERα in metastatic lesions based on its expression in primary tumor. 48% of the primary tumors with corresponding metastatic lesions were AR positive (IHC score 1–9) (A). Graphs show distribution of AR expression in the metastatic lesions from AR positive primary tumors (B) and AR negative primary tumors (C). 61% of the primary tumors with corresponding metastatic lesions were PR positive (IHC score 1–9) (D). Graphs show distribution of PR expression in the metastatic lesions from the PR positive primary tumors (E) and PR negative primary tumors (F). 52% of the primary tumors with corresponding metastatic lesions were ER positive (IHC score 4–9) (G). Graphs show distribution of ER expression in the ER positive primary tumors (H) and ER negative primary tumors (I). Expression patterns in individual metastases from AR positive patients (J) and AR negative patients (K) are shown as AR (purple), PR (green) and ERα (orange) in J and K. One line of circles represents one metastasis, and shows the difference in hormone receptor expression in that specific metastasis. Only patients with one or more AR positive metastases are shown. *Only primary tumors with corresponding metastases included.
Figure 3. AR status predicts prognosis in…
Figure 3. AR status predicts prognosis in endometrial cancer
Endometrial cancer patients with AR expression (scoring index 1–9) have a significantly better survival than patient with AR loss (scoring index 0) both in the whole population (A) and in the subgroup of patients with FIGO stage I and II (B).
Figure 4. High AR to ER ratio…
Figure 4. High AR to ER ratio identifies a subgroup with particularly poor survival
Patients with a high AR to ERα ratio assessed by Reverse Phase Protein Array demonstrate a particularly poor disease specific survival compared to patients with a low AR to ERα ratio (A). The group with high AR to ERα ratio had significantly higher CCP score (B) and PCNA expression (C) compared to the group with low AR to ERα ratio.

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