Epithelial-to-mesenchymal transition induced by TGF-β1 is mediated by Blimp-1-dependent repression of BMP-5.
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.
Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
Mathilde
M
Romagnoli
Karine
K
Belguise
Ziyang
Z
Yu
Xiaobo
X
Wang
Esther
E
Landesman-Bollag
David C
DC
Seldin
Dany
D
Chalbos
Sophie
S
Barillé-Nion
Pascal
P
Jézéquel
Margaret L
ML
Seldin
Gail E
GE
Sonenshein
D000818:Animals; D055417:Bone Morphogenetic Protein 5 / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D051379:Mice; D010455:Peptides / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011247:Pregnancy; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
C513345:AP1 peptide; C525814:BMP5 protein, human; D055417:Bone Morphogenetic Protein 5; D010455:Peptides; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D019908:Proto-Oncogene Proteins c-raf