Genome profiling of <it>ERBB2</it>-amplified breast cancers
<p>Abstract</p> <p>Background</p> <p>Around 20% of breast cancers (BC) show <it>ERBB2 </it>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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-10-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/10/539 |
| _version_ | 1828254405489590272 |
|---|---|
| author | Ayed Farhat Tarpin Carole Charafe-Jauffret Emmanuelle Innocenti Charlène Raynaud Stéphane Bonansea Julien Hamida Azza Adélaïde José Finetti Pascal Bekhouche Ismahane Sircoulomb Fabrice Viens Patrice Jacquemier Jocelyne Bertucci François Birnbaum Daniel Chaffanet Max |
| author_facet | Ayed Farhat Tarpin Carole Charafe-Jauffret Emmanuelle Innocenti Charlène Raynaud Stéphane Bonansea Julien Hamida Azza Adélaïde José Finetti Pascal Bekhouche Ismahane Sircoulomb Fabrice Viens Patrice Jacquemier Jocelyne Bertucci François Birnbaum Daniel Chaffanet Max |
| author_sort | Ayed Farhat |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Around 20% of breast cancers (BC) show <it>ERBB2 </it>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.</p> <p>Methods</p> <p>We defined the high resolution genome and gene expression profiles of 54 <it>ERBB2</it>-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.</p> <p>Results</p> <p>First, we identified the <it>ERBB2</it>-<it>C17orf37</it>-<it>GRB7 </it>genomic segment as the minimal common 17q12-q21 amplicon, and <it>CRKRS </it>and <it>IKZF3 </it>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 <it>ERBB2</it>-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) <it>ERBB2</it>-amplified BCs were different. The WNT/β-catenin signaling pathway was involved in ER- <it>ERBB2</it>-amplified BCs, and <it>PVT1 </it>and <it>TRPS1 </it>were candidate oncogenes associated with ER+ <it>ERBB2</it>-amplified BCs. The size of the <it>ERBB2 </it>amplicon was different in inflammatory (IBC) and non-inflammatory BCs. <it>ERBB2</it>-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 <it>ERBB2 </it>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 <it>ERBB2</it>-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with <it>ERBB2</it>-amplified tumors.</p> <p>Conclusion</p> <p>We have shown that ER+ and ER- <it>ERBB2</it>-amplified BCs are different, distinguished <it>ERBB2 </it>amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.</p> |
| first_indexed | 2024-04-13T01:57:24Z |
| format | Article |
| id | doaj.art-982e4bb11c4d46a680bd188f03665a20 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-13T01:57:24Z |
| publishDate | 2010-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-982e4bb11c4d46a680bd188f03665a202022-12-22T03:07:43ZengBMCBMC Cancer1471-24072010-10-0110153910.1186/1471-2407-10-539Genome profiling of <it>ERBB2</it>-amplified breast cancersAyed FarhatTarpin CaroleCharafe-Jauffret EmmanuelleInnocenti CharlèneRaynaud StéphaneBonansea JulienHamida AzzaAdélaïde JoséFinetti PascalBekhouche IsmahaneSircoulomb FabriceViens PatriceJacquemier JocelyneBertucci FrançoisBirnbaum DanielChaffanet Max<p>Abstract</p> <p>Background</p> <p>Around 20% of breast cancers (BC) show <it>ERBB2 </it>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.</p> <p>Methods</p> <p>We defined the high resolution genome and gene expression profiles of 54 <it>ERBB2</it>-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.</p> <p>Results</p> <p>First, we identified the <it>ERBB2</it>-<it>C17orf37</it>-<it>GRB7 </it>genomic segment as the minimal common 17q12-q21 amplicon, and <it>CRKRS </it>and <it>IKZF3 </it>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 <it>ERBB2</it>-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) <it>ERBB2</it>-amplified BCs were different. The WNT/β-catenin signaling pathway was involved in ER- <it>ERBB2</it>-amplified BCs, and <it>PVT1 </it>and <it>TRPS1 </it>were candidate oncogenes associated with ER+ <it>ERBB2</it>-amplified BCs. The size of the <it>ERBB2 </it>amplicon was different in inflammatory (IBC) and non-inflammatory BCs. <it>ERBB2</it>-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 <it>ERBB2 </it>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 <it>ERBB2</it>-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with <it>ERBB2</it>-amplified tumors.</p> <p>Conclusion</p> <p>We have shown that ER+ and ER- <it>ERBB2</it>-amplified BCs are different, distinguished <it>ERBB2 </it>amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.</p>http://www.biomedcentral.com/1471-2407/10/539 |
| spellingShingle | Ayed Farhat Tarpin Carole Charafe-Jauffret Emmanuelle Innocenti Charlène Raynaud Stéphane Bonansea Julien Hamida Azza Adélaïde José Finetti Pascal Bekhouche Ismahane Sircoulomb Fabrice Viens Patrice Jacquemier Jocelyne Bertucci François Birnbaum Daniel Chaffanet Max Genome profiling of <it>ERBB2</it>-amplified breast cancers BMC Cancer |
| title | Genome profiling of <it>ERBB2</it>-amplified breast cancers |
| title_full | Genome profiling of <it>ERBB2</it>-amplified breast cancers |
| title_fullStr | Genome profiling of <it>ERBB2</it>-amplified breast cancers |
| title_full_unstemmed | Genome profiling of <it>ERBB2</it>-amplified breast cancers |
| title_short | Genome profiling of <it>ERBB2</it>-amplified breast cancers |
| title_sort | genome profiling of it erbb2 it amplified breast cancers |
| url | http://www.biomedcentral.com/1471-2407/10/539 |
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