Subtype-Conditioned NRF2–KEAP1 Signaling in Breast Cancer: A Narrative Review and Hypothesis-Generating Framework from Chemoprevention to Therapy Resistance

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.