Abstract
IntroductionThe G protein-coupled estrogen receptor (GPER) is a novel estrogen receptor that mediates proliferative effects induced by estrogen but also by tamoxifen. The aim of our study was to analyze the frequency of GPER in a large collective of primary invasive breast carcinomas, with special emphasis on the subcellular expression and to evaluate the association with clinicopathological parameters and patient overall survival.MethodsThe tissue microarrays from formalin-fixed, paraffin embedded samples of primary invasive breast carcinomas (n = 981) were analyzed for GPER expression using immunohistochemistry. Expression data were compared to the clinicopathological parameters and overall survival. GPER localization was also analyzed in two immortalized breast cancer cell lines T47D and MCF7 by confocal immunofluorescence microscopy.ResultsA predominantly cytoplasmic GPER expression was found in 189 carcinomas (19.3%), whereas a predominantly nuclear expression was observed in 529 cases (53.9%). A simultaneous comparable positive expression of both patterns was found in 32 of 981 cases (3.2%), and negative staining was detected in 295 cases (30%). Confocal microscopy confirmed the occurrence of cytoplasmic and nuclear GPER expression in T47D and MCF7. Cytoplasmic GPER expression was significantly associated with non-ductal histologic subtypes, low tumor stage, better histologic differentiation, as well as Luminal A and B subtypes. In contrast, nuclear GPER expression was significantly associated with poorly differentiated carcinomas and the triple-negative subtype. In univariate analysis, cytoplasmic GPER expression was associated with better overall survival (p = 0.012).ConclusionOur data suggest that predominantly cytoplasmic and/or nuclear GPER expression are two distinct immunohistochemical patterns in breast carcinomas and may reflect different biological features, reason why these patterns should be clearly distinguished in histological evaluations. Prospective studies will be needed to assess whether the expression status of GPER in breast carcinomas should be routinely observed by clinicians, for instance, before implementing endocrine breast cancer treatment.
Highlights
The G protein-coupled estrogen receptor (GPER) is a novel estrogen receptor that mediates proliferative effects induced by estrogen and by tamoxifen
Tamoxifen and fulvestrant are used therapeutically to inhibit the 17betaestradiol signaling pathway in breast cancer, it has been shown in an immortalized human breast cancer cell line (MCF7) that these drugs lead to an agonistic activation of GPER that results in stimulated proliferation via EGFR transactivation [2]
In breast cancer cells that were negative for the classical estrogen receptors, it has been shown that estrogen or hydroxytamoxifen were able to induce cell proliferation and migration via an activation of GPER, which seems to be mainly mediated by the connective tissue growth factor (CTGF) [7]
Summary
The G protein-coupled estrogen receptor (GPER) is a novel estrogen receptor that mediates proliferative effects induced by estrogen and by tamoxifen. GPER has been experimentally showed to mediate the proliferative effects of tamoxifen in the endometrium [3]. Supporting these findings, GPER expression has been clinically correlated with tamoxifen-induced endometrial thickening and bleeding [4]. Previous studies in breast cancer patients reported an association of GPER expression with an increased metastatic potential and a poorer prognosis [5]. In breast cancer cells that were negative for the classical estrogen receptors, it has been shown that estrogen or hydroxytamoxifen were able to induce cell proliferation and migration via an activation of GPER, which seems to be mainly mediated by the connective tissue growth factor (CTGF) [7]
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