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

BACKGROUND: The hormone sensitivity of melanoma and the role of 'classical' estrogen receptor (ER) alpha and beta 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, ERalpha and ERbeta 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 ERbeta were co-expressed. GPER/ERbeta 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 ERbeta was similar (78.4% versus 81.6%; p=0.8504), while in NPAM ERbeta was the representative ER (60.5% versus 27.9%; p=0.0010) without gender difference (59.1% versus 61.9%). GPER/ERbeta positive melanomas were associated with lower Breslow thickness, lower mitotic rate and higher presence of peritumoral lymphocyte infiltration (PLI) compared to GPER/ERbeta 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 ERbeta expression in PAM, no significant difference was found in DFS between PAM and NPAM. All but one case failed to show ERalpha expression. CONCLUSIONS: The presence of GPER and its simultaneous expression with ERbeta can serve as a new prognostic indicator in a significant subpopulation of melanoma patients. This article is protected by copyright. All rights reserved