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- Title
Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells.
- Authors
Hill, A.; McFarlane, S.; Mulligan, K.; Gillespie, H.; Draffin, J. E.; Trimble, A.; Ouhtit, A.; Johnston, P. G.; Harkin, D. P.; McCormick, D.; Waugh, D. J. J
- 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).Oncogene (2006) 25, 6079–6091. doi:10.1038/sj.onc.1209628; published online 1 May 2006
- Subjects
BREAST cancer; BONE marrow; METASTASIS; TETRACYCLINE; CANCER cells; HYALURONIC acid; CELL lines
- Publication
Oncogene, 2006, Vol 25, Issue 45, p6079
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1209628