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Updated: May 2, 2026

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

Yu-Hao Huang1, Yu-Ci Tu1, Peng-Ju Chien1,2

  • 1Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan.

Oncology Research
|May 1, 2026
PubMed
Abstract

Insights

Targeting the EGFR/SRC/STAT3/HK2 pathway overcomes radioresistance in triple-negative breast cancer (TNBC). This axis sustains cancer stem cells (CSCs) via hexokinase-2 (HK2) upregulation, offering new therapeutic strategies for aggressive TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Stem Cell Research

Background:

  • Triple-negative breast cancer (TNBC) is aggressive, with poor prognosis and resistance to radiotherapy.
  • Cancer stem cells (CSCs) are crucial drivers of TNBC initiation, metastasis, and therapy resistance.
  • Identifying pathways that sustain CSCs in radioresistant TNBC is vital for developing targeted therapies.

Purpose of the Study:

  • To investigate the roles of SRC proto-oncogene (SRC) and signal transducer and activator of transcription 3 (STAT3) in radioresistance and CSC maintenance in TNBC.
  • To elucidate the molecular mechanisms underlying radioresistance and CSC survival in TNBC.

Main Methods:

  • Developed a radioresistant TNBC cell line (MDA-MB-231/231RR) and assessed CSC activity.
  • Utilized Western blotting, functional assays, SRC/STAT3 inhibitor treatments, and SRCY530F overexpression.
  • Analyzed pathways using metabolic assays, The Cancer Genome Atlas (TCGA) data, and Harmonizome gene sets.

Main Results:

  • The radioresistant 231RR cells showed enhanced CSC traits and upregulated SRC/STAT3 signaling, responding effectively to SRC/STAT3 inhibitors.
  • SRCY530F overexpression increased STAT3 activation and CSC activity; SRC/STAT3 inhibition reduced hexokinase-2 (HK2) without affecting glycolysis.
  • HK2 knockdown decreased c-MYC and OCT4; EGFR inhibition by gefitinib suppressed the EGFR/SRC/STAT3/HK2 axis.

Conclusions:

  • The EGFR/SRC/STAT3/HK2 axis drives radioresistance and CSC maintenance in TNBC through HK2 upregulation.
  • HK2 promotes stemness via non-metabolic mechanisms, not broad metabolic shifts.
  • Targeting this axis presents a promising strategy to overcome radioresistance and improve TNBC treatment outcomes.
Keywords:
Hexokinase-2 (HK2)SRCTriple-negative breast cancercancer stem cellsradioresistancesignal transducer and activator of transcription 3 (STAT3)

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