Subtype-Conditioned NRF2-KEAP1 Signaling in Breast Cancer: A Narrative Review and Hypothesis-Generating Framework from Chemoprevention to Therapy Resistance.
4 affiliations
- 1Department of Radiology, Gyeongsang National University Hospital and College of Medicine, 79 Gangnam-ro, Jinju 52727, Republic of Korea.
- 2Department of Radiology, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea.
- 3Institute of Medical Science, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea.
- 4Biomedical Research Institute, Gyeongsang National University Hospital, 79 Gangnam-ro, Jinju 52727, Republic of Korea.
Abstract
NRF2 (nuclear factor erythroid 2-related factor 2) and its repressor KEAP1 (Kelch-like ECH-associated protein 1) govern the antioxidant response; their role in breast cancer is paradoxical: the same program that prevents malignant transformation can later drive survival and therapy resistance. We argue that this behavior is not a fixed switch but a continuum conditioned by molecular subtype, disease stage, and therapeutic context. Synthesizing primary mechanistic and clinical evidence, we find that NRF2 activation is predominantly non-mutational and that its pathological dependence is strongest not in triple-negative breast cancer (TNBC) as a whole but in a candidate redox-addicted subset-defined by nuclear NRF2 with reduced cytoplasmic KEAP1 protein, cystine/SLC7A11 reliance, and active ferroptosis defense. This subset is hypothesis-generating rather than validated: current support derives chiefly from a single tissue microarray cohort and cell-line studies, and the co-occurrence and prevalence of its features remain unestablished. NRF2-driven suppression of ferroptosis is one major, tractable mechanism of resistance among several. We frame these as directions for future research: no NRF2-directed intervention is ready for biomarker-guided selection, and systemic NRF2 inhibition risks on-target toxicity, because NRF2 also protects normal tissues from oxidative stress.
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BibTeX
@article{choi2026subtypeconditioned,
title = {{Subtype-Conditioned NRF2-KEAP1 Signaling in Breast Cancer: A Narrative Review and Hypothesis-Generating Framework from Chemoprevention to Therapy Resistance.}},
author = {Hye Young Choi and Hayeong Kwon and Young-Sool Hah},
journal = {Antioxidants (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/antiox15101223},
url = {https://europepmc.org/article/MED/42939797},
note = {CC BY},
}
RIS
TY - JOUR
TI - Subtype-Conditioned NRF2-KEAP1 Signaling in Breast Cancer: A Narrative Review and Hypothesis-Generating Framework from Chemoprevention to Therapy Resistance.
AU - Hye Young Choi
AU - Hayeong Kwon
AU - Young-Sool Hah
PY - 2026
DA - 2026/09/22
JO - Antioxidants (Basel, Switzerland)
DO - 10.3390/antiox15101223
UR - https://europepmc.org/article/MED/42939797
AB - NRF2 (nuclear factor erythroid 2-related factor 2) and its repressor KEAP1 (Kelch-like ECH-associated protein 1) govern the antioxidant response; their role in breast cancer is paradoxical: the same program that prevents malignant transformation can later drive survival and therapy resistance. We argue that this behavior is not a fixed switch but a continuum conditioned by molecular subtype, disease stage, and therapeutic context. Synthesizing primary mechanistic and clinical evidence, we find that NRF2 activation is predominantly non-mutational and that its pathological dependence is strongest not in triple-negative breast cancer (TNBC) as a whole but in a candidate redox-addicted subset-defined by nuclear NRF2 with reduced cytoplasmic KEAP1 protein, cystine/SLC7A11 reliance, and active ferroptosis defense. This subset is hypothesis-generating rather than validated: current support derives chiefly from a single tissue microarray cohort and cell-line studies, and the co-occurrence and prevalence of its features remain unestablished. NRF2-driven suppression of ferroptosis is one major, tractable mechanism of resistance among several. We frame these as directions for future research: no NRF2-directed intervention is ready for biomarker-guided selection, and systemic NRF2 inhibition risks on-target toxicity, because NRF2 also protects normal tissues from oxidative stress.
SN - 2076-3921
ER -