Beyond molecular tumor heterogeneity: protein synthesis takes control

Ramon y Cajal, Santiago; Castellvi, Josep; Hümmer, Stefan; Peg, Vicente; Pelletier, Jerry; Sonenberg, Nahum

In the past decade, by analyzing more than 2500 human tumor samples [55] [56] [57] [58] [59] [60] , we have assessed the expression of membrane receptors such as EGFR and HER2, components of the RAS/RAF/ERK and PI3K/AKT/mTOR pathways, and their effectors such as p70S6K, 4E-BP1, eIF4E, and p- Fig. 3 a-h Invasive ductal carcinoma a-g (×200), h (×400). Immunohistochemistry for a p-ERK1/2, b p-S6, c p-4E-BP1, d p-eIF4E, e p-AKT, and f p-mTOR. g, h GLUT-1 Immunohistochemistry was performed as described previously [58] using the following primary antibodies: p-eIF4E (Abcam, Ab76256), p-4E-BP1 (T37/46) (Cell Signaling, #2855), pS6 (S235/236) (Cell Signaling, #2211), p-ERK1/2 (T202/Y204) (Cell Signaling, #9101), p-mTOR (Ser2448) (Cell Signaling #2971); p-Akt (Ser473) (Cell Signaling #3787), GLUT-1 (Abcam, Ab652) eIF4E. We have found that increased amounts of total or p-eIF4E, as well as p-4E-BP1, are associated with malignant progression and adverse prognosis in several tumors, including breast, lung, ovary, endometrium, glioma, and prostate cancers, regardless of the upstream oncogenic alterations (Figs. 3 and 4) [22] . Other groups have confirmed the prognostic importance of these factors in additional tumor types (Table 1) , including colon cancer [61, 62] , nasopharyngeal carcinoma [63] , hepatocellular carcinoma [64] , astrocytomas [65] , lung cancer [66, 67] , and melanoma [68] . Importantly, eIF4E is a central regulator of metastatic progression [69] [70] [71] (Fig. 4) .