The Runx transcriptional co-activator, CBFβ, is essential for invasion of breast cancer cells

Background: The transcription factor Runx2 has an established role in cancers that metastasize to bone. In metastatic breast cancer cells Runx2 is overexpressed and contributes to the invasive capacity of the cells by regulating the expression of several invasion genes. CBF beta is a transcriptional co-activator that is recruited to promoters by Runx transcription factors and there is considerable evidence that CBF beta is essential for the function of Runx factors. However, overexpression of Runx1 can partially rescue the lethal phenotype in CBF beta-deficient mice, indicating that increased levels of Runx factors can, in some situations, overcome the requirement for CBF beta. Since Runx2 is overexpressed in metastatic breast cancer cells, and there are no reports of CBF beta expression in breast cells, we sought to determine whether Runx2 function in these cells was dependent on CBF beta. Such an interaction might represent a viable target for therapeutic intervention to inhibit bone metastasis. Results: We show that CBF beta is expressed in the metastatic breast cancer cells, MDA-MB-231, and that it associates with Runx2. Matrigel invasion assays and RNA interference were used to demonstrate that CBF beta contributes to the invasive capacity of these cells. Subsequent analysis of Runx2 target genes in MDA-MB-231 cells revealed that CBF beta is essential for the expression of Osteopontin, Matrixmetalloproteinase-13, Matrixmetalloproteinase-9, and Osteocalcin but not for Galectin-3. Chromatin immunoprecipitation analysis showed that CBF beta is recruited to both the Osteopontin and the Galectin-3 promoters. Conclusions: CBF beta is expressed in metastatic breast cancer cells and is essential for cell invasion. CBF beta is required for expression of several Runx2-target genes known to be involved in cell invasion. However, whilst CBF beta is essential for invasion, not all Runx2-target genes require CBFv. We conclude that CBF beta is required for a subset of Runx2-target genes that are sufficient to maintain the invasive phenotype of the cells. These findings suggest that the interaction between Runx2 and CBF beta might represent a viable target for therapeutic intervention to inhibit bone metastasis.