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An oncogenic role of eIF3e/INT6 in human breast cancer

Oncogene volume 29, pages 4080–4089 (2010)Cite this article

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Abstract

Altered expression of the eukaryotic translation initiation factor 3 (eIF3) subunit eIF3e/INT6 has been described in various types of human cancer, but the nature of its involvement in tumorigenesis is not yet clear. Using immunohistochemical analysis of 81 primary breast cancers, we found that high tumor grade correlated significantly with elevated cytoplasmic eIF3e level in epithelial tumor cells. Analysis of protein synthesis after siRNA-mediated knockdown in breast cancer cell lines indicated that eIF3e is not required for bulk translation. Microarray analysis of total and polysomal RNAs nonetheless identified distinct sets of mRNAs regulated either positively or negatively by eIF3e; functional classification of these revealed a marked enrichment of genes involved in cell proliferation, invasion and apoptosis. Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Finally, eIF3e-depleted breast carcinoma cells showed reduced in vitro invasion and proliferation. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. It regulates the translation, and in some cases abundance, of mRNAs involved in key aspects of cancer cell biology.

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Acknowledgements

We thank Ben Thomas and Sasha Akoulitchev for help and advice with 2D liquid chromatography, Cheng Han for help with the statistical analysis, Dan Scott and other members of the laboratory for their comments on the article. This work was supported by Cancer Research UK, the Association for International Cancer Research and the Wellcome Trust (through grant 075491/Z/04 to JR).

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Authors and Affiliations

  1. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    M Grzmil, R G Capper, N J Saunders & C J Norbury

  2. Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK

    T Rzymski, M Milani & A L Harris

  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    A Salhan & J Ragoussis

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  1. M Grzmil
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Correspondence to C J Norbury.

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Grzmil, M., Rzymski, T., Milani, M. et al. An oncogenic role of eIF3e/INT6 in human breast cancer. Oncogene 29, 4080–4089 (2010). https://doi.org/10.1038/onc.2010.152

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