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Open Access Highly Accessed Research article

Genome profiling of ERBB2-amplified breast cancers

Fabrice Sircoulomb1, Ismahane Bekhouche1, Pascal Finetti1, José Adélaïde1, Azza Ben Hamida1, Julien Bonansea1, Stéphane Raynaud1, Charlène Innocenti1, Emmanuelle Charafe-Jauffret124, Carole Tarpin3, Farhat Ben Ayed5, Patrice Viens34, Jocelyne Jacquemier12, François Bertucci134, Daniel Birnbaum1 and Max Chaffanet1*

Author Affiliations

1 Marseille Cancer Research Center, UMR891 Inserm, Institut Paoli-Calmettes, Department of Molecular Oncology, Marseille, France

2 Department of BioPathology, Institut Paoli-Calmettes, Marseille, France

3 Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France

4 Université de la Méditerranée, Marseille, France

5 Department of Medical Oncology, Salah Azaiz Institute, Tunis, Tunisia

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BMC Cancer 2010, 10:539  doi:10.1186/1471-2407-10-539

Published: 8 October 2010

Abstract

Background

Around 20% of breast cancers (BC) show ERBB2 gene amplification and overexpression of the ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs, genomically and biologically heterogeneous, may help understand their behavior and design new therapeutic strategies.

Methods

We defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. Expression of ERBB2, phosphorylated ERBB2, EGFR, IGF1R and FOXA1 proteins was assessed by immunohistochemistry to evaluate the functional ERBB2 status and identify co-expressions.

Results

First, we identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common 17q12-q21 amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, GISTIC analysis identified 17 other genome regions affected by copy number aberration (CNA) (amplifications, gains, losses). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/β-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2 amplicon was different in inflammatory (IBC) and non-inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. IHC results showed (i) a linear relationship between ERBB2 gene amplification and its gene and protein expressions with a good correlation between ERBB2 expression and phosphorylation status; (ii) a potential signaling cross-talk between EGFR or IGF1R and ERBB2, which could influence response of ERBB2-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with ERBB2-amplified tumors.

Conclusion

We have shown that ER+ and ER- ERBB2-amplified BCs are different, distinguished ERBB2 amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.