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

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...

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Autores principales: Modelska, A, Turro, E, Russell, R, Beaton, J, Sbarrato, T, Spriggs, K, Miller, J, Gräf, S, Provenzano, E, Blows, F, Pharoah, P, Caldas, C, Le Quesne, J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669741/
https://www.ncbi.nlm.nih.gov/pubmed/25611378
http://dx.doi.org/10.1038/cddis.2014.542
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author Modelska, A
Turro, E
Russell, R
Beaton, J
Sbarrato, T
Spriggs, K
Miller, J
Gräf, S
Provenzano, E
Blows, F
Pharoah, P
Caldas, C
Le Quesne, J
author_facet Modelska, A
Turro, E
Russell, R
Beaton, J
Sbarrato, T
Spriggs, K
Miller, J
Gräf, S
Provenzano, E
Blows, F
Pharoah, P
Caldas, C
Le Quesne, J
author_sort Modelska, A
collection PubMed
description 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.
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spelling pubmed-46697412015-12-08 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, K Miller, J Gräf, S Provenzano, E Blows, F Pharoah, P Caldas, C Le Quesne, J Cell Death Dis Original Article 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. Nature Publishing Group 2015-01 2015-01-22 /pmc/articles/PMC4669741/ /pubmed/25611378 http://dx.doi.org/10.1038/cddis.2014.542 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
spellingShingle Original Article
Modelska, A
Turro, E
Russell, R
Beaton, J
Sbarrato, T
Spriggs, K
Miller, J
Gräf, S
Provenzano, E
Blows, F
Pharoah, P
Caldas, C
Le Quesne, J
The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape
title The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape
title_full The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape
title_fullStr The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape
title_full_unstemmed The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape
title_short The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape
title_sort malignant phenotype in breast cancer is driven by eif4a1-mediated changes in the translational landscape
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669741/
https://www.ncbi.nlm.nih.gov/pubmed/25611378
http://dx.doi.org/10.1038/cddis.2014.542
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