PT - JOURNAL ARTICLE AU - Rojo, Federico AU - Najera, Laura AU - Lirola, José AU - Jiménez, José AU - Guzmán, Marta AU - Sabadell, M. Dolors AU - Baselga, Jose AU - Cajal, Santiago Ramon y TI - 4E-Binding Protein 1, A Cell Signaling Hallmark in Breast Cancer that Correlates with Pathologic Grade and Prognosis AID - 10.1158/1078-0432.CCR-06-1560 DP - 2007 Jan 01 TA - Clinical Cancer Research PG - 81--89 VI - 13 IP - 1 4099 - http://clincancerres.aacrjournals.org/content/13/1/81.short 4100 - http://clincancerres.aacrjournals.org/content/13/1/81.full SO - Clin Cancer Res2007 Jan 01; 13 AB - 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.