Abstract
BackgroundThe 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. CBFβ is a transcriptional co-activator that is recruited to promoters by Runx transcription factors and there is considerable evidence that CBFβ is essential for the function of Runx factors. However, overexpression of Runx1 can partially rescue the lethal phenotype in CBFβ-deficient mice, indicating that increased levels of Runx factors can, in some situations, overcome the requirement for CBFβ. Since Runx2 is overexpressed in metastatic breast cancer cells, and there are no reports of CBFβ expression in breast cells, we sought to determine whether Runx2 function in these cells was dependent on CBFβ. Such an interaction might represent a viable target for therapeutic intervention to inhibit bone metastasis.ResultsWe show that CBFβ 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 CBFβ contributes to the invasive capacity of these cells. Subsequent analysis of Runx2 target genes in MDA-MB-231 cells revealed that CBFβ is essential for the expression of Osteopontin, Matrixmetalloproteinase-13, Matrixmetalloproteinase-9, and Osteocalcin but not for Galectin-3. Chromatin immunoprecipitation analysis showed that CBFβ is recruited to both the Osteopontin and the Galectin-3 promoters.ConclusionsCBFβ is expressed in metastatic breast cancer cells and is essential for cell invasion. CBFβ is required for expression of several Runx2-target genes known to be involved in cell invasion. However, whilst CBFβ is essential for invasion, not all Runx2-target genes require CBFβ. We conclude that CBFβ 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 CBFβ might represent a viable target for therapeutic intervention to inhibit bone metastasis.
Highlights
The transcription factor Runx2 has an established role in cancers that metastasize to bone
We demonstrate that CBFβ is expressed in metastatic breast cancer cells and that it is essential for cell invasion
We conclude that CBFβ is required for a subset of Runx2-target genes that are sufficient to maintain the invasive phenotype of the cells
Summary
The transcription factor Runx has an established role in cancers that metastasize to bone. Since Runx is overexpressed in metastatic breast cancer cells, and there are no reports of CBFβ expression in breast cells, we sought to determine whether Runx function in these cells was dependent on CBFβ Such an interaction might represent a viable target for therapeutic intervention to inhibit bone metastasis. Ablation of Runx expression in metastatic breast cancer cells, MDA-MB-231, resulted in down-regulation of metastatic genes and reduced the invasive capacity of the cells [12]. It is not known if the increased expression of Runx observed in metastatic breast cancer cells is sufficient to regulate gene expression independently of CBFβ. It is not known if CBFβ is expressed in metastatic breast cancer cells
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