1. Epithelial-to-mesenchymal transition induced by TGF-β1 is mediated by Blimp-1-dependent repression of BMP-5.
- Author
-
Romagnoli M, Belguise K, Yu Z, Wang X, Landesman-Bollag E, Seldin DC, Chalbos D, Barillé-Nion S, Jézéquel P, Seldin ML, and Sonenshein GE
- Subjects
- Animals, Bone Morphogenetic Protein 5 genetics, Breast Neoplasms metabolism, Cell Line, Tumor, Female, Gene Knockout Techniques, Humans, Immunoblotting, MCF-7 Cells, Mice, Peptides metabolism, Positive Regulatory Domain I-Binding Factor 1, Pregnancy, Proto-Oncogene Proteins c-raf metabolism, Repressor Proteins biosynthesis, Repressor Proteins deficiency, Repressor Proteins genetics, Transfection, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Bone Morphogenetic Protein 5 metabolism, Breast Neoplasms pathology, Epithelial-Mesenchymal Transition drug effects, Repressor Proteins metabolism, Transforming Growth Factor beta1 pharmacology
- Abstract
Induction of epithelial-to-mesenchymal transition (EMT) by TGF-β1 requires Ras signaling. We recently identified the transcriptional repressor Blimp-1 (PRDM1) as a downstream effector of the NF-κB, RelB/Bcl-2/Ras-driven pathway that promotes breast cancer cell migration. As the RelB/Blimp-1 pathway similarly required Ras signaling activation, we tested whether Blimp-1 plays a role in TGF-β1-mediated EMT. Here, TGF-β1 treatment of untransformed NMuMG mammary epithelial and MDA-MB-231 breast cancer cells was shown to induce Blimp-1 expression, which promoted an EMT signature and cell migration. TGFB1 and BLIMP1 RNA levels were correlated in patient breast tumors. BLIMP1 gene transcription was activated by TGF-β1 via a c-Raf (RAF1) to AP-1 pathway. Blimp-1 induced expression of the EMT master regulator Snail (SNAI1) via repressing BMP-5, which inhibited Snail expression upon TGF-β1 treatment. Interestingly, a similar cascade was observed during postnatal mouse mammary gland development. RelB expression was detected early in pregnancy followed progressively by Blimp-1 and then Snail; whereas, BMP-5 levels were high in nulliparous and regressing glands. Finally, lower BMP5 RNA levels were detected in patient breast tumors versus normal tissues, and correlated with cancer recurrence. Thus, the Ras effector Blimp-1 plays an essential role in TGF-β1-induced EMT via repression of BMP-5 in breast cancer.
- Published
- 2012
- Full Text
- View/download PDF