Abstract
Simple SummaryTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and has a poor prognosis and higher recurrence rate due to ineffective therapy. Even with newly approved therapeutics, only limited TNBC patients could have benefited from the regimens. Protein disulfide isomerase (PDI) has been of great interest as a potential therapeutic target for cancers due to its impacts on tumor progression, metastasis, and clinical outcomes. Here, we discuss the roles of PDI members in breast cancers such as TNBC and the PDI inhibitors studied in breast cancer research.Protein disulfide isomerase (PDI) is the endoplasmic reticulum (ER)’s most abundant and essential enzyme and serves as the primary catalyst for protein folding. Due to its apparent role in supporting the rapid proliferation of cancer cells, the selective blockade of PDI results in apoptosis through sustained activation of UPR pathways. The functions of PDI, especially in cancers, have been extensively studied over a decade, and recent research has explored the use of PDI inhibitors in the treatment of cancers but with focus areas of other cancers, such as brain or ovarian cancer. In this review, we discuss the roles of PDI members in breast cancer and PDI inhibitors used in breast cancer research. Additionally, a few PDI members may be suggested as potential molecular targets for highly metastatic breast cancers, such as TNBC, that require more attention in future research.
Highlights
Introduction iationsBreast cancer is the most common malignant tumor and the second leading cause of cancer-related death in women
A similar mechanism by extracellular Protein disulfide isomerase (PDI) is crucial for the activation of matrix metalloproteinases (MMPs) that are overexpressed in higher grades of breast cancer tumors and contribute to breast cancer metastasis [45,90]
PDI members are upregulated alongside other unfolded protein response (UPR) proteins in cancers, highlighting the importance of PDI in regulating cancer cell survival
Summary
TNBC is an aggressive disease with fewer specific targets due to the lack of any receptor expression. The only approved PARP inhibitor for TNBC is Talazoparib (Talzenna, Pfizer) [23] It is approved as a single-agent therapy for the treatment of HER2-negative breast cancer with a germline BRCA1 mutation, and it shows significant improvement in progression-free survival compared to standard chemotherapy. PD-L1 can cause T-Cell anergy (inactivation of T-cells as an immune tolerance mechanism), enabling TNBCs to evade immune detection Checkpoint inhibitors such as Atezolizumab, an anti-PD-L1 monoclonal antibody, and a PD-1 receptor targeting humanized monoclonal antibody, such as Pembrolizumab, have been tested with neoadjuvant chemotherapy [31,32]. These combinations have shown significant improvement in overall survival.
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