4E-Binding Protein 1, A Cell Signaling Hallmark in Breast Cancer that Correlates with Pathologic Grade and Prognosis
- 1 January 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 13 (1), 81-89
- https://doi.org/10.1158/1078-0432.ccr-06-1560
Abstract
Purpose: Cell signaling pathways include a complex myriad of interconnected factors from the membrane to the nucleus, such as erbB family receptors and the phosphoinositide-3-kinase/Akt/mTOR and Ras-Raf-ERK cascades, which drive proliferative signals, promote survival, and regulate protein synthesis. Experimental Design: To find pivotal factors in these pathways, which provide prognostic information in malignancies, we studied 103 human breast tumors with an immunohistochemical profile, including total and phosphorylated (p) proteins: human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor, extracellular signal-regulated kinase 1/2, Akt, 4E-binding protein 1 (4EBP1), eukaryotic initiation factor 4E, phosphorylated ribosomal protein S6 kinase 1, phosphorylated ribosomal protein S6, and Ki67. Western blot and reverse lysate protein arrays were also done in a subset of tumors. Results: Significantly, activation of the phosphoinositide-3-kinase/Akt/mTOR cascade was detected in a high proportion of tumors (41.9%). Tumors with HER2 overexpression showed higher p-Akt as compared with negative tumors (P < 0.001). Levels of p-Akt correlated with the downstream molecules, p-4EBP1 (P = 0.001) and p-p70S6K (P = 0.05). Although 81.5% of tumors expressed p-4EBP1, in 16.3% of these tumors, concomitant activation of the upstream factors was not detected. Interestingly, p-4EBP1 was mainly expressed in poorly differentiated tumors (P < 0.001) and correlated with tumor size (P < 0.001), presence of lymph node metastasis (P = 0.002), and locoregional recurrences (P = 0.002). Coexpression of p-4EBP1 and p-eIF4G correlated with a high tumor proliferation rate (P = 0.012). Conclusion: In this study, p-4EBP1 was the main factor in signaling pathways that associate with prognosis and grade of malignancy in breast tumors. Moreover, p-4EBP1 was detected in both HER2-positive and HER2-negative tumors. This factor seems to be a channeling point at which different upstream oncogenic alterations converge and transmit their proliferative signal, modulating protein translation.Keywords
This publication has 46 references indexed in Scilit:
- Activation of the Akt/Mammalian Target of Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in Breast CancersClinical Cancer Research, 2004
- TOR signaling in mammalsJournal of Cell Science, 2004
- The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcomeThe Journal of Pathology, 2004
- The tor pathway: a target for cancer therapyNature Reviews Cancer, 2004
- A census of human cancer genesNature Reviews Cancer, 2004
- Cell cycle-dependent phosphorylation of the translational repressor eIF-4E binding protein-1 (4E-BP1)Current Biology, 2001
- Molecular portraits of human breast tumoursNature, 2000
- The Hallmarks of CancerCell, 2000
- Gatekeepers and caretakersNature, 1997
- p53, the Cellular Gatekeeper for Growth and DivisionCell, 1997