A role for Runx2 in normal mammary gland and breast cancer bone metastasis

Abstract

The transcription factor Runx2 is essential for the formation of the skeleton. It has therefore primarily been considered as a specific regulator of bone genes. However, mice containing a LacZ insertion at the Runx2 locus also revealed expression in the nascent mammary epithelium. Reports of Runx2 expression in breast cancer cell lines, combined with the fact that breast cancers preferentially metastasise to bone, have also hinted at a potential role for Runx2 in the formation of bone metastasese. These initial observations have prompted further analysis of Runx2 function in mammary epithelial cells and recent findings have demonstrated that Runx2 does indeed contribute to the ability of metastatic breast cancer cell lines to form osteolytic bone lesions. In addition, evidence is accumulating that Runx2 has a role in the regulation of normal mammary gland gene expression and recent data demonstrate that it regulates transcription of the mammary gland-specific gene, b-casein. In this article I discuss recent advances that link Runx2 with normal mammary epithelial cell function and the development of bone metastasese in breast cancer.

An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation

“…More important, the disclosure of DDR2/Runx2 signaling may facilitate the identification of more DDR2 target genes in other cells or tissues that express functional Runx2, such as breast cancer cells, sperm, and brain. (56)(57)(58)(59) Therefore, it can be envisioned that the infertility phenotype in Ddr2 mutant mice might be associated with impaired Runx2 activity. (34) Among several candidate protein kinases, only ERK MAPK signaling was linked to DDR2 activation.…”

The ATF/CREB Family of Transcription Factors in Breast Cancer

“…Other transcription factors involved in breast cancer include snail, which blocks E-cadherin transcription (Cano and others 2000); CBP/p300, a transcriptional co-activator involved in HER2 expression (Wang and others 2001); STAT6, which blocks the immune response to breast cancer (Sinha and others 2005); and Fra-1, whose overexpression leads to increased invasion in breast cancer (Mizutani and others 2004). Like PEA3, Runx2 is also involved in breast cancer metastasis, specifically, metastasis to bone (Shore 2005). Its targets include collagenase-3 and BSP, which are upregulated in metastatic breast cancer cells (Shore 2005).…”

Of mice and (wo)men: Mouse models of breast cancer metastasis to bone

“…(32) The transcription factor Runx2, involved in osteogenesis, is also present in breast cancer. (33)(34)(35) Moreover, within the bone marrow, disseminated breast cancer cells encounter additional mitogens and other factors that normally support hematopoiesis and adult stem cells. Together these factors in the bone environment present the disseminated carcinoma cells with an array of chemokines, growth factors, and antiapoptotic factors, too numerous to list here, that support colonization and thus the development of macroscopic metastases.…”