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ARTICLE

Targeting SRC/STAT3 Signaling Impairs Cancer Stem Cell Activity by Downregulation of Hexokinase-2 in Radioresistant Triple-Negative Breast Cancer Cells

Yu-Hao Huang1, Yu-Ci Tu1, Peng-Ju Chien1,2, An-Jie Lee1, Chia-Liang Lin3, Shao-Ti Li4, Yueh-Chun Lee4,5,*, Wen-Wei Chang1,6,*
1 Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
2 Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
3 Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
4 Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung, Taiwan
5 School of Medicine, Chung Shan Medical University, Taichung, Taiwan
6 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
* Corresponding Author: Yueh-Chun Lee. Email: email; Wen-Wei Chang. Email: email
(This article belongs to the Special Issue: Discovery of a Potent Antitumor Agent: Mechanistic Insights and Therapeutic Potential)

Oncology Research https://doi.org/10.32604/or.2026.075190

Received 27 October 2025; Accepted 04 February 2026; Published online 03 March 2026

Abstract

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and resistance to conventional therapies, including radiotherapy. Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance in TNBC. Identifying pathways sustaining CSCs in radioresistant TNBC is key for targeted therapies. This study examines SRC proto-oncogene (SRC) and the signal transducer and activator of transcription 3 (STAT3) activation in radioresistance and CSC maintenance. Methods: A radioresistant MDA-MB-231 TNBC cell line (231RR) was developed and compared to the parental line for CSC activity and self-renewal. Western blotting assessed molecular changes; functional assays followed SRC and STAT3 inhibitor treatment. SRCY530F overexpression and hexokinase-2 (HK2) knockdown evaluated roles in CSC activity and signaling. Pathways were analyzed via metabolic assays, The Cancer Genome Atlas (TCGA) breast cancer datasets, and Harmonizome gene sets. Results: 231RR cells exhibited enhanced CSC traits and upregulated SRC/STAT3 signaling, with heightened sensitivity to SRC/STAT3 inhibitors. Forced expression of SRCY530F in parental cells boosted STAT3 activation and CSC activity. SRC/STAT3 inhibition reduced HK2 without impairing glycolysis. HK2 knockdown decreased MYC proto-oncogene (c-MYC) and octamer-binding transcription factor-4 (OCT4). Finally, the suppression of epidermal growth factor receptor (EGFR) activation by gefitinib resulted in the inhibition of the SRC/STAT3/HK2 axis. TCGA data linked SRC to glycolytic signatures in breast cancer. Conclusions: The EGFR/SRC/STAT3/HK2 axis drives radioresistance and CSC maintenance in TNBC via HK2 upregulation. HK2 promotes stemness mainly through non-metabolic means, not broad metabolic shifts. Targeting this pathway could overcome radioresistance and enhance TNBC outcomes.

Keywords

Triple-negative breast cancer; radioresistance; cancer stem cells; SRC; signal transducer and activator of transcription 3 (STAT3); Hexokinase-2 (HK2)

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