Open Access

ARTICLE

Extracellular Signal-Regulated Kinase and Reactive Oxygen Species Regulate PD-L1 to Promote Migration and Proliferation of Triple-Negative Breast Cancer MDA-MB-231 Cells

Ching-Chun Ho¹, Yen-Cheng Chen^1,2, Wei-Liang Lean¹, Wen-Sheng Wu^1,*

1 Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
2 School of Medicine, Tzu Chi University, Hualien, Taiwan

* Corresponding Author: Wen-Sheng Wu. Email:

(This article belongs to the Special Issue: Integrative Strategies in Cancer Therapy)

Oncology Research 2026, 34(8), 17 https://doi.org/10.32604/or.2026.077693

Received 15 December 2025; Accepted 18 May 2026; Issue published 16 July 2026

Abstract

Objectives: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), as well as protein kinase B (AKT), are potential therapeutic targets for TNBC. Programmed death-ligand 1 (PD-L1) is implicated in TNBC progression and is associated with AKT and ERK signaling pathways. In addition, reactive oxygen species (ROS) act upstream of MAPK/AKT and PD-L1. In this study, we aimed to clarify the role of PD-L1 in TNBC progression and to delineate the underlying signaling mechanisms. Methods: Western blotting and reverse transcription–polymerase chain reaction were used to analyze protein and mRNA levels, respectively. Transwell migration and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays were used to assess cell migration and proliferation, respectively. Results: The ERK inhibitor (PD98059) suppressed MDA-MB-231 cell migration but not proliferation, whereas PD-L1 siRNA and the ROS scavenger dithiothreitol (DTT) reduced both cell migration and proliferation. However, PD-L1 siRNA and DTT did not reduce the activities of ERK, JNK, or AKT. Whereas PD98059 and DTT suppressed PD-L1 protein expression, PD-L1 mRNA expression could be reduced by DTT only. Taken together, ROS and ERK may activate different pathways to regulate PD-L1 expression and MDA-MB-231 cell progression. Consistently, DTT combined with PD98059 additively inhibited MDA-MB-231 cell migration. Similar observations were noted in another TNBC cell line, Hs578T, which exhibits motility, but not in MDA-MB-453 cells, which lack motility. Conclusion: Since PD-L1 appears to function downstream of ERK and ROS and is required for TNBC progression, co-targeting both ERK and ROS signaling pathways may represent a promising therapeutic strategy for TNBC.

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Keywords

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Supplementary Material

Supplementary Material File

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