Protein Disulfide Isomerase A1 (PDIA1) regulates breast cancer cell immunorecognition in a manner dependent on redox state: PDIA1 in the regulation of breast cancer cell immunorecognition

The oxidoreductases protein disulphide isomerases (PDI) are implicated in the regulation of a variety of biological processes including the modulation of endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), the ER - mitochondria communication and the balance between pro-survival and pro-death pathways. This study investigated the role of the PDIA1 family member in breast carcinogenesis. The results showed that this enzyme exerted pro-apoptotic effects in the estrogen receptor (ERα) positive breast cancer MCF-7 and pro-survival in the triple negative breast cancer (TNBC) MDA-MB-231 cells. ATP generation was upregulated in PDIA1-silenced MCF-7 cells and downregulated in PDIA1-silenced MDA-MB-231 cells in a manner dependent on the cellular redox status. Furthermore, MCF-7 and MDA-MB-231 cells in the presence of PDIA1 expressed higher surface levels of the non-classical human leukocyte antigen (HLA-G) under oxidative stress conditions. Interrogation of the METABRIC datasets showed that low PDIA1 and high HLA-G mRNA expression levels correlated with longer survival in both ERα positive and ERα negative stage 2 breast cancer patients. In addition, analysis of the PDIA1 versus the HLA-G mRNA ratio in the subgroup of the living stage 2 breast cancer patients exhibiting low PDIA1 and high HLA-G mRNA levels revealed that the longer the survival time high PDIA1 and low HLA-G mRNA ratio appeared to be predominantly in the ERα positive breast cancer patients whereas in the same subgroup of the ERα negative breast cancer mainly this ratio is low PDIA1 and high HLA-G mRNA. Taken together these results provide evidence supporting the view that PDIA1 is linked to several hallmarks of breast cancer pathways including the process of antigen processing and presentation and tumor immunorecognition.