Abstract
We have recently shown that the adaptor protein p140Cap regulates tumor properties in terms of cell motility and growth. Here, by using the highly metastatic rat adenocarcinoma cell line MTLn3-epidermal growth factor receptor (EGFR), we assess the role of p140Cap in metastasis formation. Orthotopic transplantation of MTLn3-EGFR cells over-expressing p140Cap in Rag2−/−γc−/− mice resulted in normal primary tumor growth compared with the controls. Strikingly, p140Cap over-expression causes an 80% inhibition in the number of lung metastases. p140Cap over-expressing cells display a 50% reduction in directional cell migration, an increased number and size of focal adhesions, and a strong impairment in the ability to invade in a 3D matrix. p140Cap over-expression affects EGFR signaling and tyrosine phosphorylation of cortactin in response to EGF stimulation. Intriguingly, p140Cap associates with cortactin via interaction with its second proline-rich domain to the cortactin SH3 domain. The phosphomimetic cortactin tyrosine 421 mutant rescues migration and invasive properties in p140Cap over-expressing cells. Taken together, these data demonstrate that p140Cap suppresses the invasive properties of highly metastatic breast carcinoma cells by inhibiting cortactin-dependent cell motility.
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Acknowledgements
We thank Stefan Huveneers for help with the in vitro angiogenesis assay. This work was supported by EU FP7 Metafight project, AIRC, MUR (PRIN), Regione Piemonte – Progetti Sanità, Oncoprot, PiSTEM, Druidi and CIPE, Compagnia San Paolo, Torino, the Dutch Cancer Society (UL 2006-3521, UL 2007-3860 and UL 2010-4670) and the Netherlands Genomics Initiative grant to the Netherlands Toxicogenomics Center grant.
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Damiano, L., Le Dévédec, S., Di Stefano, P. et al. p140Cap suppresses the invasive properties of highly metastatic MTLn3-EGFR cells via impaired cortactin phosphorylation. Oncogene 31, 624–633 (2012). https://doi.org/10.1038/onc.2011.257
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DOI: https://doi.org/10.1038/onc.2011.257
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