Common human malignancies acquire derangements of the translation initiation complex, eIF4F, but their functional significance is unknown. Hypophosphorylated 4E-BP proteins negatively regulate eIF4F assembly by sequestering its mRNA cap binding component eIF4E, whereas hyperphosphorylation abrogates this function. We found that breast carcinoma cells harbor increases in the eIF4F constituent eIF4GI and hyperphosphorylation of 4E-BP1 which are two alterations that activate eIF4F assembly. Ectopic expression of eIF4E 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, eIF4F activation is an essential component of the malignant phenotype in breast carcinoma.
Bibliographical noteFunding Information:
We thank Robert Kratzke (University of Minnesota) and Igor Rosenwald (University of New Mexico) for helpful discussions. We also thank Dr. Stempfer (Lawrence Berkeley National Laboratory) for HMEC cell lines and Patricia Jung (University of Minnesota) for excellent assistance with tumor immunohistochemistry. This work was supported by DOD DAMD17-99-9228 and NIH/NCI 5 UO1 CA91220-02 grants to V.A.P. and NIH grants HL073719 and AI50162 to P.B.B.