Robust eIF4B levels undermine invasive growth and immune evasion mechanisms in murine triple negative breast cancer models.

Abstract

Abstract Dysregulated protein synthesis is seen in many aggressive cancers, including metastatic breast cancer. However, the specific contributions of certain translation initiation factors to in vivo disease remain undefined. This is particularly true of eIF4B, an RNA-binding protein and cofactor of the RNA helicase eIF4A and associated eIF4F cap-binding complex. While eIF4A, eIF4G, and eIF4E are known to contribute to the progression of many cancer types, the role played by eIF4B in breast cancer remains relatively unclear. We therefore explored how naturally divergent and experimentally modulated eIF4B levels impact tumor growth and progression in murine triple negative breast cancer (TNBC) models. Surprisingly, we found that higher eIF4B levels in mouse and human breast cancers were associated with less aggressive phenotypes. shRNA-mediated eIF4B knockdown in TNBC lines failed to markedly alter proliferation and global translation in cells grown in vitro and only modestly hindered primary mammary tumor growth in mice. However, eIF4B knockdown significantly enhanced invasive growth in vitro and exacerbated both tumor burden and mortality relative to nontargeting shRNA controls in a model of metastatic disease. Deposited patient data reinforced a link between high eIF4B levels and better outcomes. Interestingly, in vitro and in vivo studies associated low eIF4B expression with more formidable immune evasion. These findings suggest that eIF4B levels impact metastatic disease in part through immunomodulatory mechanisms beyond the factor’s traditional role supporting eIF4/F directed translation. Future studies should explore the impact of these findings for personalizing treatment decisions and developing future therapies.