Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity

Abstract

Increased eukaryotic translation initiation factor 4E (eIF4E) expression occurs in many cancers, and makes fundamental contributions to carcinogenesis by stimulating the expression of cancer-related genes at post-transcriptional levels. This key role is highlighted by the facts that eIF4E levels can predict prognosis, and that eIF4E is an established therapeutic target. However, eIF4E activity is a complex function of expression levels and phosphorylation statuses of eIF4E and eIF4E-binding proteins (4E-BPs). Our hypothesis was that the combined analyses of these pathway components would allow insights into eIF4E activity and its influence on cancer. We have determined expression levels of eIF4E, 4E-BP1, 4E-BP2 and phosphorylated 4E-BP1 within 424 breast tumours, and have carried out analyses to combine these and relate the product to patient survival, in order to estimate eIF4E activity. We show that this analysis gives greater prognostic insights than that of eIF4E alone. We show that eIF4E and 4E-BP expression are positively associated, and that 4E-BP2 has a stronger influence on cancer behaviour than 4E-BP1. Finally, we examine eIF4E, estimated eIF4E activity, and phosphorylated 4E-BP1 as potential predictive biomarkers for eIF4E-targeted therapies, and show that each determines selection of different patient groups. We conclude that eIF4E's influence on cancer survival is modulated substantially by 4E-BPs, and that combined pathway analyses can estimate functional eIF4E.

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

“…Indeed, most of the direct inhibitors of the eIF machinery are targeted toward eIF4E (28). Moreover, eIF4E and its associated binding proteins have been shown to correlate with survival duration in FBC, where cases with high expression of eIF4E relative to its binding proteins had significantly worse survival (20). Our results corroborate these and other findings where elevated eIF4E expression predicts poor survival in FBC (21,29,30).…”

“…The role of initiation factors in the progression to a malignant phenotype is reported in many cancers, including, breast, head and neck, liver, prostate, bladder, gastric, colon, ovarian, glioma, lymphoma, non-small cell lung carcinoma, cervical, small intestine, and melanoma (20,(23)(24)(25). This has highlighted eIFs, notably eIF4E, as indicative of poor prognosis.…”

“…IHC was conducted as described previously, using well-validated antibodies (20), including eIF1 (Abcam; ab118979, 1:200), eIF2 (Abcam; ab32157, 1:150), eIF3 (Abcam; ab171419, 1:150), eIF4E (Santa…”

The effect of p-4E-BP1 and p-eIF4E on cell proliferation in a breast cancer model

“…Moreover, eIF4E activation is significantly related to reduced patient survival in human prostate cancer, and lung cancer (5). eIF4E can be regulated postranscriptionally by two different mechanisms: binding to translational repressor 4E-BPs and phosphorylation by MNKs (14)(15)(16). Although eIF4E phosphorylation on Ser209 was discovered some time ago, it remains unclear whether phosphorylation increases or decreases eIF4E affinity for the cap-structure.…”

Regulation of protein synthesis and the role of eIF3 in cancer

“…There are numerous examples of tumors where eIF4E levels are substantially higher than normal. Indeed, combined analysis of eIF4E and 4E-BP expression is a strong prognostic indicator of breast cancer (39).…”