Original Research Article
Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells
Article first published online: 18 APR 2013
Copyright © 2013 Wiley Periodicals, Inc.
Journal of Cellular Physiology
Volume 228, Issue 8, pages 1784–1792, August 2013
How to Cite
Pande, S., Browne, G., Padmanabhan, S., Zaidi, S. K., Lian, J. B., van Wijnen, A. J., Stein, J. L. and Stein, G. S. (2013), Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells. J. Cell. Physiol., 228: 1784–1792. doi: 10.1002/jcp.24339
- Issue published online: 18 APR 2013
- Article first published online: 18 APR 2013
- Accepted manuscript online: 6 FEB 2013 07:57AM EST
- Manuscript Accepted: 24 JAN 2013
- Manuscript Received: 14 JAN 2013
- National Institutes of Health. Grant Numbers: P01 CA082834, P01 AR048818, R01 AR039588, 5P01 CA140043
The serine/threonine kinase Akt/PKB promotes cancer cell growth and invasion through several downstream targets. Identification of novel substrates may provide new avenues for therapeutic intervention. Our study shows that Akt phosphorylates the cancer-related transcription factor Runx2 resulting in stimulated DNA binding of the purified recombinant protein in vitro. Pharmacological inhibition of the PI3K/Akt pathway in breast cancer cells reduces DNA-binding activity of Runx2 with concomitant reduction in the expression of metastasis-related Runx2 target genes. Akt phosphorylates Runx2 at three critical residues within the runt DNA-binding domain to enhance its in vivo genomic interactions with a target gene promoter, MMP13. Mutation of these three phosphorylation sites reduces Runx2 DNA-binding activity. However, Akt signaling does not appear to interefere with CBFβ-Runx2 interactions. Consequently, expression of multiple metastasis-related genes is decreased and Runx2-mediated cell invasion is supressed. Thus, our work identifies Runx2 as a novel and important downstream mediator of the PI3K/Akt pathway that is linked to metastatic properties of breast cancer cells. J. Cell. Physiol. 228: 1784–1792, 2013. © 2013 Wiley Periodicals, Inc.