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BMC Cancer. 2012; 12: 74.
Published online Feb 22, 2012. doi:  10.1186/1471-2407-12-74
PMCID: PMC3342900
Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer
Roxana Schillaci,#1 Pablo Guzmán,#2 Florencia Cayrol,1 Wendy Beguelin,1 María C Díaz Flaqué,1 Cecilia J Proietti,1 Viviana Pineda,3 Jorge Palazzi,4 Isabel Frahm,5 Eduardo H Charreau,1 Esteban Maronna,5 Juan C Roa,2 and Patricia V Elizaldecorresponding author1,6
1Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina
2Departamento de Anatomía Patológica (BIOREN) y, Universidad de La Frontera, Temuco, Chile
3Departamento de Cirugía, Facultad de Medicina, Universidad de La Frontera, Temuco, Chile
4Universidad Abierta Interamericana (UAI), Rosario, Argentina
5Servicio de Patología, Sanatorio Mater Dei, Buenos Aires, Argentina
6Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), Obligado 2490, Buenos Aires 1428, Argentina
corresponding authorCorresponding author.
#Contributed equally.
Roxana Schillaci: rschillaci/at/ibyme.conicet.gov.ar; Pablo Guzmán: pguzman/at/ufro.cl; Florencia Cayrol: flor_cayrol/at/hotmail.com; Wendy Beguelin: web2002/at/med.cornell.edu; María C Díaz Flaqué: diazflaquemaria/at/ibyme.conicet.gov.ar; Cecilia J Proietti: cproietti/at/ibyme.conicet.gov.ar; Viviana Pineda: vpineda/at/ufro.cl; Jorge Palazzi: jpalazzi/at/iictlabs.com; Isabel Frahm: frahm.isabel/at/gmail.com; Eduardo H Charreau: echarreau/at/conicet.gov.ar; Esteban Maronna: emaronna/at/hotmail.com; Juan C Roa: jcroa/at/ufro.cl; Patricia V Elizalde: patriciaelizalde/at/ibyme.conicet.gov.ar
Received November 3, 2011; Accepted February 22, 2012.
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.
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