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.
