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Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets

TURNER, N ; LAMBROS, M. B ; ASHWORTH, A ; VAN DE VIJVER, M. J ; REIS, J. S ; HORLINGS, H. M ; PEARSON, A ; SHARPE, R ; NATRAJAN, R ; GEYER, F. C ; VAN KOUWENHOVE, M ; KREIKE, B ; MACKAY, A

Oncogene, 2010-04, Vol.29 (14), p.2013-2023 [Periódico revisado por pares]

Basingstoke: Nature Publishing Group

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Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets
Autor: TURNER, N ; LAMBROS, M. B ; ASHWORTH, A ; VAN DE VIJVER, M. J ; REIS, J. S ; HORLINGS, H. M ; PEARSON, A ; SHARPE, R ; NATRAJAN, R ; GEYER, F. C ; VAN KOUWENHOVE, M ; KREIKE, B ; MACKAY, A
Assuntos: 1-Phosphatidylinositol 3-kinase ; AKT protein ; Animals ; Apoptosis ; Biological and medical sciences ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell activation ; Cell Line, Tumor ; Cell lines ; Cell physiology ; Cell Survival ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Comparative Genomic Hybridization ; Cytogenetics ; DNA microarrays ; Fibroblast growth factor receptor 2 ; Fibroblast growth factor receptors ; Fundamental and applied biological sciences. Psychology ; Gene Amplification ; Gene Dosage - genetics ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genomics ; Gynecology. Andrology. Obstetrics ; Humans ; Hybridization ; Ligands ; Mammary gland diseases ; Medical sciences ; Molecular and cellular biology ; Molecular biology ; Oncology ; Phosphatidylinositol 3-Kinases - metabolism ; Receptor Protein-Tyrosine Kinases - metabolism ; Receptor, Fibroblast Growth Factor, Type 2 - genetics ; Reproducibility of Results ; RNA-mediated interference ; Signal Transduction ; Therapeutic applications ; Therapeutic targets ; Tumors
É parte de: Oncogene, 2010-04, Vol.29 (14), p.2013-2023
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: Triple negative breast cancers (TNBCs) have a relatively poor prognosis and cannot be effectively treated with current targeted therapies. We searched for genes that have the potential to be therapeutic targets by identifying genes consistently overexpressed when amplified. Fifty-six TNBCs were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH), of which 24 were subjected to genome-wide gene expression analysis. TNBCs were genetically heterogeneous; no individual focal amplification was present at high frequency, although 78.6% of TNBCs harboured at least one focal amplification. Integration of aCGH and expression data revealed 40 genes significantly overexpressed when amplified, including the known oncogenes and potential therapeutic targets, FGFR2 (10q26.3), BUB3 (10q26.3), RAB20 (13q34), PKN1 (19p13.12) and NOTCH3 (19p13.12). We identified two TNBC cell lines with FGFR2 amplification, which both had constitutive activation of FGFR2. Amplified cell lines were highly sensitive to FGFR inhibitor PD173074, and to RNAi silencing of FGFR2. Treatment with PD173074 induced apoptosis resulting partly from inhibition of PI3K-AKT signalling. Independent validation using publicly available aCGH data sets revealed FGFR2 gene was amplified in 4% (6/165) of TNBC, but not in other subtypes (0/214, P=0.0065). Our analysis demonstrates that TNBCs are heterogeneous tumours with amplifications of FGFR2 in a subgroup of tumours.
Editor: Basingstoke: Nature Publishing Group
Idioma: Inglês

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Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets

TURNER, N ; LAMBROS, M. B ; ASHWORTH, A ; VAN DE VIJVER, M. J ; REIS, J. S ; HORLINGS, H. M ; PEARSON, A ; SHARPE, R ; NATRAJAN, R ; GEYER, F. C ; VAN KOUWENHOVE, M ; KREIKE, B ; MACKAY, A

Basingstoke: Nature Publishing Group

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