Abstract
IntroductionTranslation initiation is activated in cancer through increase in eukaryotic initiation factor 4E (eIF4E), eIF4G, phosphorylated eIF4E-binding protein (p4E-BP1) and phosphorylated ribosomal protein S6 (pS6), and decreased programmed cell death protein 4 (pdcd4), a translational inhibitor. Further, translation elongation is deregulated though alterations in eukaryotic elongation factor 2 (eEF2) and eEF2 kinase (eEF2K). We sought to determine the association of these translational aberrations with clinical-pathologic factors and survival outcomes in hormone receptor-positive breast cancer.MethodsPrimary tumors were collected from 190 patients with Stage I to III hormone receptor-positive breast cancer. Expression of eIF4E, eIF4G, 4E-BP1, p4E-BP1 T37/46, p4E-BP1 S65, p4E-BP1 T70, S6, pS6 S235/236, pS6 S240/244, pdcd4, eEF2 and eEF2K was assessed by reverse phase protein arrays. Univariable and multivariable analyses for recurrence-free survival (RFS) and overall survival (OS) were performed.ResultsHigh eEF2, S6, pS6 S240/244, p4E-BP1 T70, and low pdcd4 were significantly associated with node positivity. Median follow-up for living patients was 96 months.High p4E-BP1 T36/47, p4E-BP1 S65, p4E-BP1 T70 and 4E-BP1 were associated with worse RFS. High p4E-BP1 T70 and pS6 S235/236, and low pdcd4, were associated with worse OS. In multivariable analysis, in addition to positive nodes, p4E-BP1 S65 remained a significant predictor of RFS (HR = 1.62, 95% CI = 1.13-2.31; P = 0.008). In addition to age, pS6 S235/236 (HR = 1.73, 95% CI = 1.03-2.90, P = 0.039), eEF2K (HR = 2.19, 95% CI = 1.35-3.56, P = 0.002) and pdcd4 (HR = 0.42, 95% CI = 0.25-0.70, P = 0.001) were associated with OS.ConclusionsIncreased pS6, p4E-BP1, eEF2K and decreased pdcd4 are associated with poor prognosis in hormone receptor-positive breast cancer, suggesting their role as prognostic markers and therapeutic targets.
Highlights
Translation initiation is activated in cancer through increase in eukaryotic initiation factor 4E, eukaryotic initiation factor 4G (eIF4G), phosphorylated eIF4E-binding protein (p4E-BP1) and phosphorylated ribosomal protein S6, and decreased programmed cell death protein 4, a translational inhibitor
We determined whether expression/phosphorylation of specific translational factors correlated with clinical-pathologic characteristics
Nodal status and T stage were added to the model, in addition to positive nodes, phosphorylated eIF4E-binding protein 1 (p4E-BP1) S65 remained a significant predictor of recurrence-free survival (RFS) (hazard ratio (HR) = 1.62, 95% confidence interval (CI) = 1.13-2.31, P = 0.008)
Summary
Translation initiation is activated in cancer through increase in eukaryotic initiation factor 4E (eIF4E), eIF4G, phosphorylated eIF4E-binding protein (p4E-BP1) and phosphorylated ribosomal protein S6 (pS6), and decreased programmed cell death protein 4 (pdcd4), a translational inhibitor. Translation elongation is deregulated though alterations in eukaryotic elongation factor 2 (eEF2) and eEF2 kinase (eEF2K). The most recognized alteration in translation is the overexpression of eukaryotic initiation factor 4E (eIF4E), the mRNA 5’cap-binding protein. Cap-dependent mRNAs initiate translation through interaction with the cap-dependent initiation complex eIF4F, comprised of eIF4E, scaffold protein eIF4G, and ATP-dependent helicase eIF4A (Figure 1) [2]. EIF4E overexpression leads to selective translation of a subset of mRNA such as cyclin D1, Bcl-2, Bcl-xL, and vascular endothelial growth factor, enhances nucleocytoplasmic transport for selected mRNA such as cyclin D1 and mediates Akt activation by upregulating Nijmegen breakage syndrome protein 1, an Akt pathway activator [1,3,4,5,6,7]. Formation of the eIF4F complex determines the sensitivity to chemotherapy, as well as anticancer drugs targeting HER2 and EGFR [10]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.