Abstract
The progression of cancers from primary tumors to invasive and metastatic stages accounts for the overwhelming majority of cancer deaths. Understanding the molecular events which promote metastasis is thus critical in the clinic. Translational control is emerging as an important factor in tumorigenesis. The messenger RNA (mRNA) cap-binding protein eIF4E is an oncoprotein that has an important role in cancer initiation and progression. eIF4E must be phosphorylated to promote tumor development. However, the role of eIF4E phosphorylation in metastasis is not known. Here, we show that mice in which eukaryotic translation initiation factor 4E (eIF4E) cannot be phosphorylated are resistant to lung metastases in a mammary tumor model, and that cells isolated from these mice exhibit impaired invasion. We also demonstrate that transforming growth factor-beta (TGFβ) induces eIF4E phosphorylation to promote the translation of Snail and Mmp-3 mRNAs, and the induction of epithelial-to-mesenchymal transition (EMT). Furthermore, we describe a new model wherein EMT induced by TGFβ requires translational activation via the non-canonical TGFβ signaling branch acting through eIF4E phosphorylation.
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Acknowledgements
This work was by supported by The Susan G. Komen Breast Cancer Foundation (IIR12224057), and the Canadian Cancer Society (2010-700377) to NS. WHM was supported by the Cancer Research Society (2012-17280). LF was supported by PCFA#YI-0310. NS is a Howard Hughes Medical Institute Senior International Scholar. WHM is a Chercheur National of Fonds de la Recherche en Santé du Quebec (FRSQ). NR was supported by scholarships from the Fonds de la Recherche en Santé du Québec (20874), the Canadian Institutes of Health Research (220151) and the Vanier Canada Graduate Scholarship (267839). OL is supported by the Swedish Research Council, the Swedish Cancer Society and the Wallenberg Academy Fellows Program. We thank I Topisirovic for advice; C Zakaria, A Sylvestre, S Perreault and C Lister for technical assistance, N Siddiqui for critical reading of the manuscript and S Ramón y Cajal (the Vall d’Hebron University Hospital, Barcelona, Spain) for his support and insights into tumor heterogeneity. We thank the Animal Facility and the Histology Facility at the Goodman Cancer Research Centre for mouse work and tissue processing.
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Robichaud, N., del Rincon, S., Huor, B. et al. Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene 34, 2032–2042 (2015). https://doi.org/10.1038/onc.2014.146
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DOI: https://doi.org/10.1038/onc.2014.146
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