title: Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer.
abstract: BACKGROUND
  The biological relevance of nuclear ErbB-2/HER2 (NuclErbB-2) presence in breast tumors remains unexplored. In this study we assessed the clinical significance of ErbB-2 nuclear localization in primary invasive breast cancer. The reporting recommendations for tumor marker prognostic studies (REMARK) guidelines were used as reference.
  
  
  METHODS
  Tissue microarrays from a cohort of 273 primary invasive breast carcinomas from women living in Chile, a Latin American country, were examined for membrane (MembErbB-2) and NuclErbB-2 expression by an immunofluorescence (IF) protocol we developed. ErbB-2 expression was also evaluated by immunohistochemistry (IHC) with a series of antibodies. Correlation between NuclErbB-2 and MembErbB-2, and between NuclErbB-2 and clinicopathological characteristics of tumors was studied. The prognostic value of NuclErbB-2 in overall survival (OS) was evaluated using Kaplan-Meier method, and Cox model was used to explore NuclErbB-2 as independent prognostic factor for OS.
  
  
  RESULTS
  The IF protocol we developed showed significantly higher sensitivity for detection of NuclErbB-2 than IHC procedures, while its specificity and sensitivity to detect MembErbB-2 were comparable to those of IHC procedures. We found 33.6% NuclErbB-2 positivity, 14.2% MembErbB-2 overexpression by IF, and 13.0% MembErbB-2 prevalence by IHC in our cohort. We identified NuclErbB-2 positivity as a significant independent predictor of worse OS in patients with MembErbB-2 overexpression. NuclErbB-2 was also a biomarker of lower OS in tumors that overexpress MembErbB-2 and lack steroid hormone receptors.
  
  
  CONCLUSIONS
  We revealed a novel role for NuclErbB-2 as an independent prognostic factor of poor clinical outcome in MembErbB-2-positive breast tumors. Our work indicates that patients presenting NuclErbB-2 may need new therapeutic strategies involving specific blockage of ErbB-2 nuclear migration.
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
authors.forename: Roxana
authors.initials: R
authors.lastname: Schillaci
authors.forename: Pablo
authors.initials: P
authors.lastname: Guzmán
authors.forename: Florencia
authors.initials: F
authors.lastname: Cayrol
authors.forename: Wendy
authors.initials: W
authors.lastname: Beguelin
authors.forename: María C
authors.initials: MC
authors.lastname: Díaz Flaqué
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Proietti
authors.forename: Viviana
authors.initials: V
authors.lastname: Pineda
authors.forename: Jorge
authors.initials: J
authors.lastname: Palazzi
authors.forename: Isabel
authors.initials: I
authors.lastname: Frahm
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Charreau
authors.forename: Esteban
authors.initials: E
authors.lastname: Maronna
authors.forename: Juan C
authors.initials: JC
authors.lastname: Roa
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Elizalde
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism*; D002277:Carcinoma / Q000737:chemistry / Q000378:metabolism*; D002677:Chile; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D046228:Microarray Analysis; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases