Expression of G protein-coupled oestrogen receptor in melanoma and in pregnancy-associated melanoma

Background The hormone sensitivity of melanoma and the role of 'classical' oestrogen receptor (ER) alpha and beta in tumour progression have been intensively studied with rather contradictory results. The presence of 'non-classical' G protein-coupled oestrogen receptor (GPER) has not been investigated on human melanoma tissues. Objective To analyse the expression of GPER, ER alpha and ER beta 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 analysed by uni- and multivariate Cox proportional hazards regression. Results G protein-coupled oestrogen receptor was detected both in PAMs and NPAMs. In 39 of the 41 (95.1%) GPER-positive melanomas, GPER and ER beta were co-expressed. GPER/ER beta-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 ER beta was similar (78.4% vs. 81.6%; P = 0.8504), while in NPAM, ER beta was the representative ER (60.5% vs. 27.9%; P = 0.0010) without gender difference (59.1% vs. 61.9%). GPER-/ER beta-positive melanomas were associated with lower Breslow thickness, lower mitotic rate and higher presence of peritumoral lymphocyte infiltration (PLI) compared to GPER-/ER beta-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 ER beta expression in PAM, no significant difference was found in DFS between PAM and NPAM. All but one case failed to show ER alpha expression. Conclusions The presence of GPER and its simultaneous expression with ER beta can serve as a new prognostic indicator in a significant subpopulation of melanoma patients.