Journal
ONCOGENE
Volume 28, Issue 50, Pages 4444-4455Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.296
Keywords
Gab2; anchorage independence; metastasis; microarray; breast cancer
Funding
- AIRC
- EC [503438]
- CNR-MIUR
- FIRB-MIUR
- Ministero della Salute, Regione Piemonte
- Foundations CRT and 'Compagnia di San Paolo'
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Acquisition of independence from anchorage to the extracellular matrix is a critical event for onset and progression of solid cancers. To identify and characterize new genes conferring anchorage independence, we transduced MCF10A human normal breast cells with a retroviral cDNA expression library and selected them by growth in suspension. Microarray analysis targeted on library-derived transcripts revealed robust and reproducible enrichment, after selection, of cDNAs encoding the scaffolding adaptor Gab2. Gab2 was confirmed to strongly promote anchorage-independent growth when overexpressed. Interestingly, downregulation by RNA interference of endogenous Gab2 in neoplastic cells did not affect their adherent growth, but abrogated their growth in soft agar. Gab2-driven anchorage independence was found to specifically involve activation of the Src-Stat3 signaling axis. A transcriptional 'signature' of 205 genes was obtained from GAB2-transduced, anchorage-independent MCF10A cells, and found to contain two main functional modules, controlling proliferation and cell adhesion/migration/invasion, respectively. Extensive validation on breast cancer data sets showed that the GAB2 signature provides a robust prognostic classifier for breast cancer metastatic relapse, largely independent from existing clinical and genomic indicators and from estrogen receptor status. This work highlights a pivotal role for GAB2 and its transcriptional targets in anchorage-independent growth and breast cancer metastatic progression. Oncogene (2009) 28, 4444-4455; doi:10.1038/onc.2009.296; published online 19 October 2009
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