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Breast Cancer Research
Published in: Breast Cancer Research 5/2012

Open Access 01-10-2012 | Research article

Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer

Authors: Funda Meric-Bernstam, Huiqin Chen, Argun Akcakanat, Kim-Anh Do, Ana Lluch, Bryan T Hennessy, Gabriel N Hortobagyi, Gordon B Mills, Ana Maria Gonzalez-Angulo

Published in: Breast Cancer Research | Issue 5/2012

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Abstract

Introduction

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. 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.

Methods

Primary 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.

Results

High 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.

Conclusions

Increased 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.
Appendix
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Metadata
Title
Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer
Authors
Funda Meric-Bernstam
Huiqin Chen
Argun Akcakanat
Kim-Anh Do
Ana Lluch
Bryan T Hennessy
Gabriel N Hortobagyi
Gordon B Mills
Ana Maria Gonzalez-Angulo
Publication date
01-10-2012
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2012
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3343

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