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

Abstract

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.

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

“…[66][67][68][69] Upregulated cap-dependent translation liberates cells from strict dependence on adhesion. For example, ectopic eIF4E converts immortalized HMECs into cells that form colonies when cultured at low density on a plastic substratum or in soft agar, 57 but does not by itself enable tumorigenicity.…”

“…74 In a panel of aggressive human breast carcinoma cell lines, translational repressor 4E-BP1 was found to be functionally inactivated by constitutive hyperphosphorylation through Ras-dependent signal transduction pathways, suggesting that tumor cells upregulate eIF4F ways in many ways. 57 Similarly, in human lung adenocarcinoma, there is a direct relationship between tumor invasiveness and degree of eIF4E expression; and between the eIF4E/4E-BP1 ratio in stage 1 disease and mortality, 75 (Tasaburo Takasu, personal communication).…”

“…62 Mutant forms of 4E-BP1 that can not be inactivated by hyperphosphorylation-so called super 4E-BP1-stimulate apoptosis and inhibit tumorigenicity when expressed in human breast carcinoma cells. 57 Cancer cells harboring super 4E-BP1 undergo strong negative selection during propagation in vivo or in vitro. Under these circumstances, loss of 4E-BP1 expression is closely associated with gain of resistance to apoptosis and restoration of tumorigenicity.…”

“…3,4,9 Consistent with this, constitutively active wild-type 4E-BP1 reduces the expression levels of cyclin D1 and stimulates production of the cyclin D1 antagonist p27 Kip -events that are associated with suppression of breast cancer cell proliferation. 55 Similarly, introduction of hypophosphorylated forms of 4E-BP1 inhibits proliferation of rat fibroblasts 56 and human breast cancer cells 57 in a manner that depends strictly on their ability to sequester eIF4E.…”

An Australian Retrospective Study to Evaluate the Prognostic Role of p53 and eIF4E Cancer Markers in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC): Study Protocol

“…However, overexpression of eIF4E not only induces the transformation and tumorgenesis, but also initiates metastasis (De Benedetti and Graff, 2004). Overexpression of eIF4E is sufficient to develop the transformation of fibroblasts and primary epithelial cells (Avdulov et al, 2004). In a clinical trial, eIF4E overexpression indicates to increase cancer susceptibility because eIF4E transgenic mice develop lymphomas, angiosarcomas, lung carcinomas, and hepatomas (Ruggero et al, 2004).…”