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

Oncogene volume 28, pages 4444–4455 (2009)Cite this article

Abstract

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.

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Acknowledgements

We thank Barbara Martinoglio and Roberta Porporato for technical assistance. We thank Simona Destefanis, Antonella Cignetto and Michela Bruno for secretarial assistance. This research was supported by grants from AIRC, the EC (contract no. 503438 ‘TRANSFOG’), CNR-MIUR, FIRB-MIUR, Ministero della Salute, Regione Piemonte and the Foundations CRT and ‘Compagnia di San Paolo.’

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  1. A Mira and C Isella: These authors contributed equally to the work.

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  1. Department of Oncological Sciences and Laboratory of Functional Genomics, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Candiolo, Torino, Italy

    A Mira, C Isella, T Renzulli, D Cantarella, M L Martelli & E Medico

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Correspondence to E Medico.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Mira, A., Isella, C., Renzulli, T. et al. The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer. Oncogene 28, 4444–4455 (2009). https://doi.org/10.1038/onc.2009.296

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