Protein disulfide isomerase A1‑associated pathways in the development of stratified breast cancer therapies

Bakker, Emyr; Fujii, Masayuki; Krstic‑Demonacos, Marija; Demonacos, Constantinos; Alhammad, Rashed

Abstract

The oxidoreductase protein disulfide isomerase A1 (PDIA1) functions as a cofactor for many transcription factors including estrogen receptor α (ERα), nuclear factor (NF)‑κB, 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 a diverse subset of genes in the ERα‑positive vs. 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 γ (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 (ROS) and promoting carcinogenesis by inducing cell cycle progression. In the ERα(‑) breast cancer patients, PDIA1 prevented tumor development by modulating NF‑κΒ and p53 activity and cell migration and induced 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 ERα(+) and ERα(‑) breast cancer patients and could help identify therapeutic targets selectively effective in ERα(+) vs. ERα(‑) patients.

Citation

Bakker, E., Fujii, M., Krstic‑Demonacos, M., Demonacos, C., & Alhammad, R. (2022). Protein disulfide isomerase A1‑associated pathways in the development of stratified breast cancer therapies. International Journal of Oncology, 60(2), 16. https://doi.org/10.3892/ijo.2022.5306

• Journal Article Type: Article
• Acceptance Date: Dec 7, 2021
• Online Publication Date: Jan 10, 2022
• Publication Date: Feb 1, 2022
• Deposit Date: Jan 19, 2022
• Publicly Available Date: Jan 19, 2022
• Journal: International Journal of Oncology
• Print ISSN: 1019-6439
• Electronic ISSN: 1791-2423
• Publisher: Spandidos Publications
• Volume: 60
• Issue: 2
• Pages: 16
• DOI: https://doi.org/10.3892/ijo.2022.5306
• Keywords: Cancer Research, Oncology
• Publisher URL: https://doi.org/10.3892/ijo.2022.5306
• Related Public URLs: http://www.spandidos-publications.com/ijo/
• Additional Information: Additional Information : ** From Crossref journal articles via Jisc Publications Router **Journal IDs: pissn 1019-6439; eissn 1791-2423 **History: issued 10-01-2022; published_online 10-01-2022