Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells

Common human malignancies acquire derangements of the translation initiation complex, elF4F, but their functional significance is unknown. Hypophosphorylated 4E-BP proteins negatively regulate elF4F assembly by sequestering its mRNA cap binding component elF4E, whereas hyperphosphorylation abrogates this function. We found that breast carcinoma cells harbor increases in the elF4F constituent elF4GI and hyperphosphorylation of 4E-BP1 which are two alterations that activate elF4F assembly. Ectopic expression of elF4E in human mammary epithelial cells enabled clonal expansion and anchorage-independent growth. Transfer of 4E-BP1 phosphorylation site mutants into breast carcinoma cells suppressed their tumorigenicity, whereas loss of these 4E-BP1 phosphorylation site mutants accompanied spontaneous reversion to a malignant phenotype. Thus, elF4F activation is an essential component of the malignant phenotype in breast carcinoma.