The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer

Oncogene. 2009 Dec 17;28(50):4444-55. doi: 10.1038/onc.2009.296. Epub 2009 Oct 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Progression
  • Female
  • Humans
  • Neoplasm Metastasis
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins c-akt / physiology
  • STAT3 Transcription Factor / physiology
  • Signal Transduction / physiology*
  • Transcription, Genetic*
  • src-Family Kinases / physiology


  • Adaptor Proteins, Signal Transducing
  • GAB2 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt