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

Abstract

AbstractDysregulated 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 well-known to contribute to the progression of many cancer types including metastatic breast cancers, 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 well-characterized 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 the cells in vitro and only modestly hindered their growth as primary mammary tumors 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. Analysis of eIF4B levels and breast cancer patient survival reinforced a link to better outcomes. Interestingly, low eIF4B expression was also associated with more formidable immune evasion in vitro and in vivo, implicating a novel immunomodulatory role for this factor in the malignant setting that suggests a mode of action beyond its historical role as a co-activator of eIF4A/F.Significance StatementMetastasis is the leading cause of cancer-related mortality. Despite many advances in our understanding of this complex process and the molecular and cellular events involved, mechanisms that allow secondary tumors to arise and persist remain incompletely understood. Uncharacterized metastatic determinants active at the level of translational control may be exploitable as novel therapy targets or biomarkers predicting a tumor’s potential for spread and recurrence. Here we describe previously unrecognized consequences of dysregulated eIF4B levels in murine breast cancer that shed light on how this translation initiation factor contributes to disease outcomes. Our findings suggest that eIF4B levels direct metastatic risk and immune evasion, and further study should establish its value in personalized treatment decisions and development of future therapies.