Cancer-related ectopic expression of the bone-related transcription factor RUNX2 in non-osseous metastatic tumor cells is linked to cell proliferation and motility

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.

Genomic Promoter Occupancy of Runt-related Transcription Factor RUNX2 in Osteosarcoma Cells Identifies Genes Involved in Cell Adhesion and Motility

“…Our finding that RUNX2 may have functions in cell adhesion and motility of mobile osteosarcoma cells complements earlier findings obtained with both loss-of function and gain-of-function experiments in murine models (e.g. Runx2 null mouse embryonic fibroblasts and murine T cell lymphoma cells (14 -18)), as well as human breast and prostate cancer cells (45)(46)(47)(75)(76)(77)(78).…”

Runx2 expression: A mesenchymal stem marker for cancer

“…The data from the current study demonstrated an increase in the concentration of circulating cell-free Runx2 cell-free mRNA in patients with metastasis. In agreement with these results, Runx2 has been repeatedly identified as a regulator of bone metastases in breast and prostate cancer in previous studies (47)(48)(49). Bone is particularly recurrent as a target of metastasizing cells, thus a master skeletal transcription factor like Runx2 may be extremely relevant in potentiating tumour cell invasiveness of bone marrow, among others, contributing directly to the osteolysis process (38).…”

ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway

“…Runx2 is regarded as a pivotal transcription factor for the formation of the osteomimetic phenotype (39,40) and contributes to cancer cell dissemination into the blood, survival in the bone microenvironment, and stimulation of bone resorption (41,42). Expression of Runx2 target genes, including OPN, BSP, and osteocalcin, appears to confer osteomimetic features upon breast cancer cells, and is reported to play important roles in breast cancer bone metastasis (39).…”