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Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells

Oncogene volume 25, pages 6079–6091 (2006)Cite this article

Abstract

Using a validated tetracycline (tet)-regulated MCF7-founder (MCF7F) expression system to modulate expression of CD44 standard form (CD44s), we report the functional importance of CD44s and that of a novel transcriptional target of hyaluronan (HA)/CD44s signaling, EMS1/cortactin, in underpinning breast cancer metastasis. In functional experiments, tet-regulated induction of CD44s potentiated the migration and invasion of MCF7F cells through HA-supplemented Matrigel. EMS1/cortactin was identified by expression profiling as a novel transcriptional target of HA/CD44 signaling, an association validated by quantitative PCR and immunoblotting experiments in a range of breast cancer cell lines. The mechanistic basis underpinning CD44-promoted transcription of EMS1/cortactin was shown to be dependent upon a NFκB mechanism, since pharmacological inhibition of IκKinase-2 or suppression of p65 Rel A expression attenuated CD44-induced increases in cortactin mRNA transcript levels. Overexpression of a c-myc tagged murine cortactin construct in the weakly invasive, CD44-deficient MCF7F and T47D cells potentiated their invasion. Furthermore, the functional importance of cortactin to CD44s-promoted metastasis was demonstrated by selective suppression of cortactin in CD44-expressing MCF7F-B5 and MDA-MB-231 breast cancer cells using RNAi, which was shown to result in attenuated CD44-promoted invasion and CD44-promoted adhesion to bone marrow endothelial cells (BMECs).

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Acknowledgements

Microarray analysis was conducted by Dr Kevin Robertson (Genomic Technology and Informatics, University of Edinburgh). We thank Dr Stephen Moore and Dr Austin Tanney (Almac-Diagnostics, Craigavon, Northern Ireland) for statistical analysis of the microarray data, Dr George Tzircotis (Institute of Cancer Research, London) for provision of the FITC-labelled HA, Professor Thomas Parsons (University of Virginia, Charlottesville) for the gift of the c-myc-tagged cortactin construct, Dr Babbette Weksler (Cornell University, NY) for the transformed human BMEC cell line and Professor Luke O'Neill (Trinity College, Dublin) for the luciferase reporter constructs. Finally, we extend our thanks to Professor Peter Hamilton (QUB) for assistance with microscopy and imaging studies and Professor Peter Hall (QUB) for access to real-time PCR instrumentation. This work was supported by a research grant from Cancer Research UK (A4106/C11512) to DJJW.

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  1. Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast City Hospital, Belfast, Northern Ireland

    A Hill, S McFarlane, K Mulligan, H Gillespie, J E Draffin, A Trimble, A Ouhtit, P G Johnston, D P Harkin, D McCormick & D J J Waugh

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  1. A Hill
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  2. S McFarlane
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  3. K Mulligan
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Correspondence to D J J Waugh.

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Hill, A., McFarlane, S., Mulligan, K. et al. Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells. Oncogene 25, 6079–6091 (2006). https://doi.org/10.1038/sj.onc.1209628

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