Protein Disulfide Isomerase A1 (PDIA1)-associated pathways in the development of stratified breast cancer therapies: PDIA1-associated pathways in stratified breast cancer therapies

The oxidoreductase protein disulfide isomerase A1 (PDIA1) functions as a cofactor for many transcription factors including the estrogen receptor alpha (ERα), the NF-kappa B, the nuclear factor erythroid 2-like 2 (NRF2) and regulates the protein stability of the tumor suppressor p53. Taking this into account we hypothesized that PDIA1, by differentially modulating the gene expression of diverse subsets of genes in the ERα-positive versus the ERα-negative breast cancer cells, might modify dissimilar pathways in the two types of breast cancer. This hypothesis was investigated using RNA-seq data from PDIA1-silenced MCF-7 (ERα-positive) and MDA-MB-231 (ERα-negative) breast cancer cells treated with either interferon gamma (IFN-γ) or etoposide (ETO) and the obtained data were further analyzed using a variety of bioinformatic tools alongside clinical relevance assessment via Kaplan-Meier patient survival curves. The results highlighted the dual role of PDIA1 in suppressing carcinogenesis in the ERα(+) breast cancer patients by negatively regulating the response to reactive oxygen species and promoting carcinogenesis by inducing cell cycle progression. In the ERα(-) breast cancer patients PDIA1 prevents tumor development by modulating the NF-κΒ and p53 activity and cell migration and induces breast cancer progression through control of cytokine signaling and the immune response. The findings reported in this study shed light on the differential pathways regulating carcinogenesis in the ERα(+) and ERα(-) breast cancer patients and could help identify therapeutic targets selectively effective in the ERα(+) versus the ERα(-) patients.