Phosphorylated eIF2\u03b1 predicts disease-free survival in triple-negative breast cancer patients

Liang Guo,Jiong Wu,Yayun Chi,Linxiaoxi Ma,Zhiming Shao,Jingyan Xue

doi:10.1038/srep44674

Abstract

Phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), which functions as a marker of endoplasmic reticulum stress, has been reported to be associated with patient prognosis in various cancers. However, little is known about the prognostic value of p-eIF2α in breast cancer, particularly in different breast cancer subtypes. An immunohistochemistry screen for p-eIF2α was performed using a tissue microarray containing 233 tumors and paired peritumoral tissues from female patients diagnosed with breast cancer. The staining results were scored semiquantitatively, and the p-eIF2α expression level in breast cancer and its potential prognostic value were investigated. In this retrospective cohort study, we found that p-eIF2α levels were significantly upregulated in breast cancer (P < 0.001). p-eIF2α level was negatively correlated with lymph node status (P = 0.039). Survival analysis by Kaplan–Meier estimation and Cox regression showed that p-eIF2α level was correlated with better disease free survival (P = 0.026) and served as an independent prognostic factor (P = 0.046) in patients with triple-negative breast cancer. Our study revealed that p-eIF2α was upregulated in breast cancer and represented a novel predictor of prognosis in patients with triple-negative subtype.

Highlights

EIF2 comprises three subunits: α, β, and γ
Previous studies have reported detection of high p-eIF2αexpression levels in tumor samples compared with in matched noncancerous tissues, in cancers including bronchioloalveolar carcinomas of the lung[16], Hodgkin lymphoma[17], gastrointestinal carcinomas[18] and malignant melanoma[19]. Consistent with these previous findings, in this study, we found that p-eIF2αlevels are significantly higher in breast cancer than in peritumor tissues
P-eIF2αlevels reflect the severity of endoplasmic reticulum (ER) stress in tumors, indicating that ER stress plays an important role in the initiation of tumor formation

Summary

Introduction

EIF2 comprises three subunits: α, β, and γ. The α-subunit of eIF2, eIF2α, can be phosphorylated on Ser[51], thereby effectively reducing the level of active eIF2. In this way, p-eIF2αcan significantly inhibit mRNA translation initiation[8] and global protein synthesis[9]. Evidence has mounted to demonstrate that p-eIF2αupregulation is associated with tumor development and progression[10,11,12]. The role of ER stress and UPR activation in the development of breast cancer, which has www.nature.com/scientificreports/. We investigate whether p-eIF2αcould serve as a prognostic biomarker in breast cancer, with a particular focus on differences between different molecular subtypes; and provide evidence for a new therapeutic target in breast cancer

Methods

Results

Conclusion