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The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape

Modelska, A.; Turro, E.; Russell, R.; Beaton, J.; Sbarrato, T.; Spriggs, Keith; Miller, J.; Graf, S.; Provenzano, E.; Blows, F.; Pharoah, P.; Caldas, C.; Le Quesne, John

Authors

A. Modelska

E. Turro

R. Russell

J. Beaton

T. Sbarrato

J. Miller

S. Graf

E. Provenzano

F. Blows

P. Pharoah

C. Caldas

John Le Quesne



Abstract

Human mRNA DeXD/H-box helicases are ubiquitous molecular motors that are required for the majority of cellular processes that involve RNA metabolism. One of the most abundant is eIF4A, which is required during the initiation phase of protein synthesis to unwind regions of highly structured mRNA that would otherwise impede the scanning ribosome. Dysregulation of protein synthesis is associated with tumorigenesis, but little is known about the detailed relationships between RNA helicase function and the malignant phenotype in solid malignancies. Therefore, immunohistochemical analysis was performed on over 3000 breast tumors to investigate the relationship among expression of eIF4A1, the helicase-modulating proteins eIF4B, eIF4E and PDCD4, and clinical outcome. We found eIF4A1, eIF4B and eIF4E to be independent predictors of poor outcome in ER-negative disease, while in contrast, the eIF4A1 inhibitor PDCD4 was related to improved outcome in ER-positive breast cancer. Consistent with these data, modulation of eIF4A1, eIF4B and PCDC4 expression in cultured MCF7 cells all restricted breast cancer cell growth and cycling. The eIF4A1-dependent translatome of MCF7 cells was defined by polysome profiling, and was shown to be highly enriched for several classes of oncogenic genes, including G-protein constituents, cyclins and protein kinases, and for mRNAs with G/C-rich 5′UTRs with potential to form G-quadruplexes and with 3′UTRs containing microRNA target sites. Overall, our data show that dysregulation of mRNA unwinding contributes to the malignant phenotype in breast cancer via preferential translation of a class of genes involved in pro-oncogenic signaling at numerous levels. Furthermore, immunohistochemical tests are promising biomarkers for tumors sensitive to anti-helicase therapies.

Journal Article Type Article
Publication Date Jan 22, 2015
Journal Cell Death and Disease
Electronic ISSN 2041-4889
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 6
Article Number e1603
APA6 Citation Modelska, A., Turro, E., Russell, R., Beaton, J., Sbarrato, T., Spriggs, K., …Le Quesne, J. (2015). The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape. Cell Death and Disease, 6, https://doi.org/10.1038/cddis.2014.542
DOI https://doi.org/10.1038/cddis.2014.542
Publisher URL https://www.nature.com/cddis/journal/v6/n1/full/cddis2014542a.html
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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