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Abstract
IntroductionMetastatic breast cancer cells frequently and ectopically express the transcription factor RUNX2, which normally attenuates proliferation and promotes maturation of osteoblasts. RUNX2 expression is inversely regulated with respect to cell growth in osteoblasts and deregulated in osteosarcoma cells.MethodsHere, we addressed whether the functional relationship between cell growth and RUNX2 gene expression is maintained in breast cancer cells. We also investigated whether the aberrant expression of RUNX2 is linked to phenotypic parameters that could provide a selective advantage to cells during breast cancer progression.ResultsWe find that, similar to its regulation in osteoblasts, RUNX2 expression in MDA-MB-231 breast adenocarcinoma cells is enhanced upon growth factor deprivation, as well as upon deactivation of the mitogen-dependent MEK-Erk pathway or EGFR signaling. Reduction of RUNX2 levels by RNAi has only marginal effects on cell growth and expression of proliferation markers in MDA-MB-231 breast cancer cells. Thus, RUNX2 is not a critical regulator of cell proliferation in this cell type. However, siRNA depletion of RUNX2 in MDA-MB-231 cells reduces cell motility, while forced exogenous expression of RUNX2 in MCF7 cells increases cell motility.ConclusionsOur results support the emerging concept that the osteogenic transcription factor RUNX2 functions as a metastasis-related oncoprotein in non-osseous cancer cells.
Highlights
Metastatic breast cancer cells frequently and ectopically express the transcription factor RUNX2, which normally attenuates proliferation and promotes maturation of osteoblasts
Expression of RUNX2 in breast cancer cells is enhanced upon cessation of cell growth RUNX2 is normally expressed in lineage-committed mesenchymal progenitor cells with a osteogenic cell fate, but RUNX2 expression is aberrantly induced in different cancer cell types [8,9,10,11,12,13,14,15,16,17]
RUNX2 is endogenously expressed in selected breast cancer cell lines as evidenced by detection of RUNX2 protein by western blot analysis in highly malignant MDA-MB-231 breast adenocarcinoma cells, but not in
Summary
Metastatic breast cancer cells frequently and ectopically express the transcription factor RUNX2, which normally attenuates proliferation and promotes maturation of osteoblasts. Normal endogenous expression of Runx proteins is biologically linked to cell growth suppression. RUNX2 levels are selectively up regulated after mitosis during early G1 by both transcriptional and post-transcriptional mechanisms and down regulated prior to entry in S phase to avoid a cell growth delay in normal osteoblasts [23,45,46,47]. Taken together, these findings indicate that RUNX2 functions as a cell growth suppressor in primary diploid osteoblasts where the protein is endogenously expressed. RUNX2 destabilization is compromised in several osteosarcoma cell types that express constitutively high levels of RUNX2 [23,24,25,26], suggesting that bone cancer cells may bypass the growth suppressive properties of RUNX2
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