Expression of G protein-coupled estrogen receptor, GPER in melanoma and in pregnancy-associated melanoma

Abstract

Background

The hormone sensitivity of melanoma and the role of 'classical' estrogen receptor (ER) α and β in tumor progression have been intensively studied with rather contradictory results. The presence of 'non-classical' G protein-coupled estrogen receptor (GPER) has not been investigated on human melanoma tissues.

Objective

To analyze the expression of GPER, ERα and ERβ in pregnancy-associated (PAM) and in non-pregnancy associated (NPAM) melanomas in correlation with traditional prognostic markers and disease-free survival (DFS).

Methods

Receptor protein levels were tested using immunohistochemistry in 81 formalin-fixed paraffin-embedded melanoma tissues. PAMs (n=38) were compared with age- and Breslow thickness-matched cases (n=43) including non-pregnant women (NPAM-W) (n=22) and men (NPAM-M) (n=21). The association between receptor expression and DFS was analyzed by uni- and multivariate Cox proportional hazards regression.

Results

GPER was detected both in PAMs and NPAMs. In 39 of the 41 (95.1%) GPER positive melanomas GPER and ERβ were co-expressed. GPER/ERβ positive melanomas were significantly more common in PAM compared to NPAM (p=0.0001) with no significant difference between genders (p=0.4383). In PAMs the distribution of GPER and ERβ was similar (78.4% versus 81.6%; p=0.8504), while in NPAM ERβ was the representative ER (60.5% versus 27.9%; p=0.0010) without gender difference (59.1% versus 61.9%). GPER/ERβ positive melanomas were associated with lower Breslow thickness, lower mitotic rate and higher presence of peritumoral lymphocyte infiltration (PLI) compared to GPER/ERβ negative cases (p=0.0156, p=0.0036 and p=0.0001) predicting a better DFS (HR=0.785, 95% CI 0.582-1.058). Despite the significantly higher frequency of GPER and ERβ expression in PAM, no significant difference was found in DFS between PAM and NPAM. All but one case failed to show ERα expression.

Conclusions

The presence of GPER and its simultaneous expression with ERβ can serve as a new prognostic indicator in a significant subpopulation of melanoma patients.

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