Characterization of a novel regulator and predictors of sensitivity to trail-induced apoptosis in breast cancer cells

Abstract

Mesenchymal triple negative breast cancer (TNBC) cells are very sensitive to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) for reasons that are poorly understood. The purpose of this study was to characterize a negative regulator of TRAIL sensitivity in TNBC cells and potentially predictive biomarkers of TRAIL sensitivity in human TNBC. First, gp78, an ubiquitin ligase that facilitates endoplasmic reticulumassociated protein degradation, was found to negatively regulate TRAIL-induced caspases-3/7 activity and loss in viability independently of the unfolded protein response in the TNBC mesenchymal cell line MB231. Second, TNBC cell lines sensitive to drozitumab, a TRAIL pathway agonist, were found to express the mesenchymal markers vimentin and Axl. Vimentin and Axl were determined to be co-expressed in a publically available cDNA microarray dataset and by immunohistochemistry in human TNBC. These findings provide insight into a novel gp78-associated mechanism that governs sensitivity to TRAIL-induced apoptosis in breast cancer cells and demonstrate that the proteins vimentin and Axl may predict sensitivity to a TRAIL pathway agonist in TNBC and are identifiable in human TNBC, which reflects their potential utility in identifying patients who may benefit from a TRAIL pathway agonist. Collectively, these findings may aid in the selection of appropriate combinatorial therapies and the identification of TNBC-affected patients for treatment with a TRAIL pathway agonist.