The G Protein-Coupled Estrogen Receptor (GPER) Is Expressed in Two Different Subcellular Localizations Reflecting Distinct Tumor Properties in Breast Cancer

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.

GPER–novel membrane oestrogen receptor

“…The debate on the subcellular location of GPER is ongoing, with varying reports showing cell surface (49), intracellular membrane (154), and even nuclear localization (155). Moreover, receptor location may influence pathologies such as breast cancer, where the receptor resides in the nucleus of MCF7 cells but the cytoplasm of T47D breast cancer cells (156). The signaling pathways activated by GPER are also varied and opposing.…”

Genomic ancestry and ethnoracial self-classification based on 5,871 community-dwelling Brazilians (The Epigen Initiative)

“…This was to such a degree that it has been questioned whether – and how – ethnoracial classification in Brazil correlates with genomic ancestry. Previous genome studies based on up to a hundred informative markers showed conflicting results on this correlation345678.…”

G Protein–Coupled Estrogen Receptor Regulates Mammary Tumorigenesis and Metastasis

“…E2 stimulation of cells expressing GPER but lacking ERα activates the MAPK and PI3K cascades, among other pathways, increasing proliferation of many breast cancer cell lines, suggesting GPER may play a role in one or more events of breast carcinogenesis (15-17) and particularly triple negative breast cancer (18, 19). A small number of retrospective studies has examined the relationship between GPER expression in breast tumor samples and clinical outcome or its correlates.…”

“…Another investigation demonstrated an increased recurrence rate in GPER + invasive ductal breast cancers (21). More recently, a study of invasive breast cancer samples demonstrated GPER expression is an independent prognostic factor for decreased disease-free survival in patients treated exclusively with tamoxifen (22), with its cellular localization potentially playing a critical role (18). While these studies suggest a role for GPER in breast cancer, to this point no direct experimental evidence demonstrates a functional role for GPER in the initiation and/or progression of breast cancer.…”