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

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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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).

Original languageEnglish
Pages (from-to)6079-6091
Number of pages13
JournalOncogene
Volume25
Issue number45
DOIs
Publication statusPublished - Oct 5 2006

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Keywords

  • Breast cancer
  • CD44
  • Cortactin
  • Invasion
  • Metastasis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Hill, A., McFarlane, S., Mulligan, K., Gillespie, H., Draffin, J. E., Trimble, A., ... Waugh, D. J. J. (2006). Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells. Oncogene, 25(45), 6079-6091. https://doi.org/10.1038/sj.onc.1209628