deltaEF1 promotes osteolytic metastasis of MDA-MB-231 breast cancer cells by regulating MMP-1 expression.

摘要

Breast cancer metastasis is supposed to involve several stages in which epithelial-mesenchymal transition (EMT) is regarded as the mechanistic basis for the behavior of cancer cells. Our recent studies have implicated that deltaEF1, a member of the zinc finger-homeodomain transcription factor family, is required for governing both breast cancer EMT and bone remodeling, highlighting a potential role of deltaEF1 in modulating bone metastasis of breast cancer. In the present study, we further demonstrated that conditioned medium derived from deltaEF1-overexpressing MDA-MB-231 cells significantly induces osteoclast maturation and concurrently represses osteoblast differentiation and mineralization. On the contrary, conditioned medium derived from deltaEF1-interfered MDA-MB-231 cells exhibits an opposite effect, thus confirming the effect of deltaEF to mediate osteolytic metastasis of breast cancer. Furthermore, we found that, during this process, deltaEF1 remarkably up-regulates matrix metalloproteinase-1 (MMP-1) expression at both mRNA and protein levels in MDA-MB-231 cells. Importantly, the results of luciferase and CHIP assays indicated that deltaEF1 activates MMP-1 promoter activity through the AP-1 response element. Overexpression of deltaEF1 in MDA-MB-231 cells significantly increases the recruitment of the AP-1 components, c-Jun/c-Fos, to the endogenous MMP-1 promoter, which in effect could be mediated via the MAPK signaling pathway. In conclusion, these observations suggest a potent role of deltaEF1 to promote breast cancer metastasis to bone by regulating secretion of growth factors in the tumor microenvironment.