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Epithelial-to-mesenchymal transition induced by TGF-?1 is mediated by Blimp-1-dependent repression of BMP-5.


ABSTRACT: Induction of epithelial-to-mesenchymal transition (EMT) by TGF-?1 requires Ras signaling. We recently identified the transcriptional repressor Blimp-1 (PRDM1) as a downstream effector of the NF-?B, 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-?1-mediated EMT. Here, TGF-?1 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-?1 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-?1 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-?1-induced EMT via repression of BMP-5 in breast cancer.

SUBMITTER: Romagnoli M 

PROVIDER: S-EPMC3513653 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Epithelial-to-mesenchymal transition induced by TGF-β1 is mediated by Blimp-1-dependent repression of BMP-5.

Romagnoli Mathilde M   Belguise Karine K   Yu Ziyang Z   Wang Xiaobo X   Landesman-Bollag Esther E   Seldin David C DC   Chalbos Dany D   Barillé-Nion Sophie S   Jézéquel Pascal P   Seldin Margaret L ML   Sonenshein Gail E GE  

Cancer research 20121010 23


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 cance  ...[more]

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