Metastatic bone disease: Role of transcription factors and future targets

Abstract

Progression of cancer from the earliest event of cell transformation through stages of tumor growth and metastasis at a distal site involves many complex biological processes. Underlying the numerous responses of cancer cells to the tumor microenvironment which support their survival, migration and metastasis are transcription factors that regulate the expression of genes reflecting properties of the tumor cell. A number of transcription factors have been identified that play key roles in promoting oncogenesis, tumor growth, metastasis and tissue destruction. Relevant to solid tumors and leukemias, tissue-specific transcription factors that are deregulated resulting from mutations, being silenced or aberrantly expressed, have been well characterized. These are the master transcription factors of the Runx family of genes, the focus of this review, with emphasis placed on Runx2 that is abnormally expressed at very high levels in cancer cell lines that are metastatic to bone. Recent evidence has identified a correlation of Runx2 levels in advanced stages of prostate and breast cancer and demonstrated that effective depletion of Runx2 by RNA interference inhibits migration and invasive properties of the cells prevents metastatic bone disease. This striking effect is consistent with the broad spectrum of Runx2 properties in activating many genes in tumor cells that have already been established as indicators of bone metastasis in poor prognosis. Potential strategies to translate these findings for therapeutic applications are discussed.