Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer

Pablo Guzmán ,Juan Carlos Roa ,Cecilia J. Proietti ,Esteban Maronna,Viviana Pineda,Patricia V. Elizalde ,Roxana Schillaci,Wendy Béguelin ,Isabel Frahm,María Celeste Díaz Flaqué ,Jorge Palazzi,Florencia Cayrol,Eduardo H. Charreau

doi:10.1186/preaccept-1608045994629207

Abstract

BackgroundThe 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.MethodsTissue 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.ResultsThe 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.ConclusionsWe 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.

Highlights

The biological relevance of nuclear ErbB-2/HER2 (NuclErbB-2) presence in breast tumors remains unexplored
ErbB-2 nuclear localization in human breast cancers Since there are no previous reports on the clinical significance of NuclErbB-2 in breast cancer, we decided to tackle this issue first by conducting a retrospective study in a cohort of 273 primary invasive breast carcinomas from women living in Chile, a Latin American country
Our purpose was to assess the value of NuclErbB-2 as a prognostic marker within the context of the commonly used risk factors and the molecular subtype classification

Summary

Introduction

The biological relevance of nuclear ErbB-2/HER2 (NuclErbB-2) presence in breast tumors remains unexplored. The recombinant humanized anti-ErbB-2 monoclonal antibody trastuzumab is successfully used for treatment of MembErbB-2-positive and COX-2 expression in breast tumor specimens has already been reported [6,7]. An exciting and novel finding of our study was the demonstration of the direct involvement of Nuclear ErbB-2 (NuclErbB-2) in breast cancer growth [8]. These findings led us to build our hypothesis that NuclErbB-2 presence could be associated with highly proliferative breast cancer subtypes which show a poor clinical outcome. Our present results have for the first time demonstrated that NuclErbB-2 is a powerful and independent prognostic factor of poor clinical outcome in MembErbB-2-positive breast tumors

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Results

Discussion

Conclusion