PERK-Phosphorylated eIF2α Pathway Suppresses Tumor Metastasis Through Downregulating Expression of Programmed Death Ligand 1 and CXCL5 in Triple-Negative Breast Cancer

Endoplasmic reticulum (ER) stress has been reported to be associated with metastasis in many malignant tumors. PKR-like ER kinase-phosphorylated eukaryotic translation initiation factor 2 alpha (PERK-p-eIF2 alpha) pathway is one of the three main signal pathways in ER stress, however, its mechanism in regulating breast cancer (BC) relapse or metastasis was still not completely understood. Besides, drug resistance was an important factor influencing the effect of tumor treatment and whether PERK-p-eIF2 alpha pathway was involved in the drug resistance to BC treatment also needs to be explored. The authors conducted survival analysis of ER stress-related genes in the The Cancer Genome Atlas (TCGA) database to find the candidate molecule and found that eIF2 alpha was significantly correlated with relapse-free survival in BC patients, especially in the triple-negative BC (TNBC) patients. Furthermore, BC cell lines were used to study the downstream target of PERK-p-eIF2 alpha. In this study, p-eIF2 alpha could negatively regulate the expression of programmed death ligand 1 (PDL1) and C-X-C motif chemokine ligand 5 (CXCL5), which were important ligands of the immune cells such as T cells and myeloid-derived suppressor cells in the tumor microenvironment. Besides, p-eIF2 alpha expression in highly metastatic human TNBC cells after treatment of carboplatin was significantly decreased. The data indicated the possible novel immune-related mechanism of PERK-p-eIF2 alpha in regulating TNBC metastasis and drug resistance of carboplatin in highly metastatic TNBC.