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The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in
the translational landscape
#MMPMID25611378
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
2015[Jan]; 6
(1
): e1603
PMID25611378
show ga
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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