Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells
Department of Cell Biology; Cancer Center
Medical Subject Headings
Animals; Binding Sites; Breast Neoplasms; Cell Line, Tumor; Core Binding Factor Alpha 1 Subunit; Core Binding Factor beta Subunit; DNA, Neoplasm; Female; Humans; Male; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Mutagenesis, Site-Directed; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction
Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Neoplasms | Oncology
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 CBFbeta-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.
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Citation: J Cell Physiol. 2013 Aug;228(8):1784-92. doi: 10.1002/jcp.24339. Link to article on publisher's site
Pande, Sandhya; Browne, Gillian; Padmanabhan, Srivatsan; Zaidi, Kaleem; Lian, Jane B.; Van Wijnen, Andre J.; Stein, Janet L.; and Stein, Gary S., "Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells" (2013). University of Massachusetts Medical School Faculty Publications. 535.