Poster abstracts
Poster number 42 submitted by Thomas Ossevoort
Eukaryotic translation initiation factor 4B levels are negatively associated with metastatic potential and immune evasion in murine breast cancer models
Aravind Srinivasan (Department of Immunology, Roswell Park Comprehensive Cancer Center), Leila Zabihi Diba (Department of Biological Sciences, State University of New York at Buffalo), Thomas Ossevoort (Department of Biological Sciences, State University of New York at Buffalo), Joseph Barbi (Department of Immunology, Roswell Park Comprehensive Cancer Center), Sarah E. Walker (Department of Biological Sciences, State University of New York at Buffalo)
Abstract:
The primary factor responsible for most cancer mortality is the metastatic spread of malignant cells. However, the molecular determinants of metastatic growth and disease outcome in breast cancer, especially those active at the protein level, remain incompletely understood. While cancer-related over-expression of specific translation initiation factors, including the eukaryotic translation initiation factor 4 (eIF4) group of proteins, were previously implicated in as tumor-promoting, a more recent analysis of patient survival data in TCGA suggested a significant survival benefit for relatively high expression of eIF4B, an RNA-binding protein that activates the eIF4F (the cytoplasmic mRNA cap-binding-complex of eIF4A, eIF4G, and eIF4E). In line with this observation, we found that eIF4B levels were inversely related to metastatic potential in two widely used murine breast cancer models (i.e., EMT6 and 4T1). While eIF4F levels were consistent across both cell lines, eIF4B levels were much lower in the more metastatic 4T1 cells relative to the less invasive EMT6 line that displayed robust eIF4B protein levels. Interestingly, while shRNA-mediated knockdown of eIF4B failed to significantly affect the development of primary tumors after implantation in mouse mammary fat pads, both cell lines displayed increased metastatic spread upon eIF4B silencing. Preliminary findings link naturally low and experimentally suppressed eIF4B levels to a greater ability to upregulate the immune checkpoint receptor ligand PD-L1 - a well characterized mechanism of immune evasion known to be controlled by at the level of translation by the activity of other eIF4 factors. Together, these data suggest that high eIF4B levels promote a translation program that undercuts the ability of tumor cells to evade the host immune system and thrive at secondary sites. Our findings have implications for predicting the development of metastatic disease in breast cancer patients and the treatment decision making process. Further study of the translational signature associated with high and low eIF4B levels will likely inform future characterization of novel treatment targets and biomarkers.
Keywords: eIF4B