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Open Access Highly Accessed Research article

Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients

Andrea Sassen1, Justine Rochon2, Peter Wild3, Arndt Hartmann4, Ferdinand Hofstaedter1, Stephan Schwarz4 and Gero Brockhoff1*

Author Affiliations

1 Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany

2 Center for Clinical Studies, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany

3 Institute of Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland

4 Institute of Pathology, University of Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany

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Breast Cancer Research 2008, 10:R2  doi:10.1186/bcr1843

Published: 8 January 2008

Abstract

Introduction

The HER (human EGFR related) family of receptor tyrosine kinases (HER1/EGFR (epidermal growth factor receptor)/c-erbB1, HER2/c-erbB2, HER3/c-erbB3 and HER4/c-erbB4) shares a high degree of structural and functional homology. It constitutes a complex network, coupling various extracellular ligands to intracellular signal transduction pathways resulting in receptor interaction and cross-activation. The most famous family member is HER2, which is a target in Herceptin™ therapy in metastatic status and also in adjuvant therapy of breast cancer in the event of dysregulation as a result of gene amplification and resulting protein overexpression. The HER2-related HER receptors have been shown to interact directly with HER2 receptors and thereby mutually affect their activity and subsequent malignant growth potential. However, the clinical outcome with regard to total HER receptor state remains largely unknown.

Methods

We investigated HER1–HER4, at both the DNA and the protein level, using fluorescence in situ hybridisation (FISH) probes targeted to all four receptor loci and also immunohistochemistry in tissue microarrays derived from 278 breast cancer patients.

Results

We retrospectively found HER3 gene amplification with a univariate negative impact on disease-free survival (hazard ratio 2.35, 95% confidence interval 1.08 to 5.11, p = 0.031), whereas HER4 amplification showed a positive trend in overall and disease-free survival. Protein expression revealed no additional information.

Conclusion

Overall, the simultaneous quantification of HER3 and HER4 receptor genes by means of FISH might enable the rendering of a more precise stratification of breast cancer patients by providing additional prognostic information. The continuation of explorative and prospective studies on all HER receptors will be required for an evaluation of their potential use for specific therapeutic targeting with respect to individualised therapy.