Dual mechanism of delta EF1 expression regulated by bone morphogenetic protein-6 in breast cancer

The metastatic nature of breast cancer has been well recognized, yet the mechanisms through which breast cancer cells acquire their invasive properties have not been clearly elucidated. Our previous study indicates that BMP-6 restores E-cadherin-mediated EMT through repressing delta EF1 in breast cancer. However, the mechanism by which BMP-6 regulates delta EF1 expression remains unclear. In this study, we confirmed the significant role of BMP-6 in inhibiting MDA-MB-231 migration through decreasing delta EF1 expression which subsequently relieves delta EF1-mediated invasion. The inhibitory effect of BMP-6 through delta EF1 regulation was supported by an inverse correlation of BMP-6/miR-192 and delta EF1 expressions observed in both MDA-MB-231 and MCF-7 cells and clinical tumor specimens. Moreover, BMP-6 treatment or miR-192 transfection decreased the reporter activity of the BER 3'-UTR-luc, validating that delta EF1 is a target of miR-192. Meanwhile, we also found that BMP-6 acted as a potent transcriptional repressor of the human delta EF1 promoter. Mutation of the AP-1 binding site on this promoter abolished BMP-6-induced transrepression of SEN. Depletion of BMP-6 expression by RNAi resulted in a significant increase in the promoter activity of SER. Our study has provided novel findings of a dual mechanism for BMP-6-regulated delta EF1 expression in breast cancer cells, involving cross-talks between AP-1-mediated transcriptional repression and miRs-mediated translational inhibition. (C) 2008 Elsevier Ltd. All rights reserved.