title: The G protein-coupled estrogen receptor (GPER) is expressed in two different subcellular localizations reflecting distinct tumor properties in breast cancer.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  A 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).
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Gynecology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Samartzis
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.affiliation: Department of Medical Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meisel
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Varga
authors.affiliation: Department of Gynecology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fink
authors.affiliation: Department of Gynecology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Imesch
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D016016:Proportional Hazards Models; D021381:Protein Transport; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled