Nuclear factor κB signalling in breast cancer: mechanisms, crosstalk and therapeutic targeting.

Nuclear factor κB (NF-κB) is a context-dependent transcriptional network that integrates inflammatory, developmental, metabolic and genotoxic signals. In breast cancer, persistent or stimulus-coupled NF-κB activity can support proliferation, survival, epithelial-mesenchymal plasticity, invasion and therapy resistance, but the magnitude and biological consequences of activation differ across molecular subtypes and cellular compartments. This review critically examines canonical and non-canonical NF-κB signalling, emphasizing IKK/NEMO-dependent IκBα turnover, NIK-IKKα-dependent p100 processing, ubiquitin-dependent signalosome assembly, feedback control and context-specific NF-κB dimer composition. We then examine subtype-specific regulation in luminal A, luminal B, HER2-enriched and basal-like/triple-negative breast cancer, including crosstalk with ERα, HER2-PI3K-AKT, IL-1/TNF, RANK/RANKL and DNA-damage responses. Particular attention is given to tumour-microenvironmental signalling, macrophage heterogeneity, immune regulation, metabolic stress and treatment resistance. Evidence is explicitly separated into in vitro, in vivo, clinical-correlative and interventional levels. Therapeutic opportunities include upstream pathway inhibition, proteasome blockade, selective NIK/IKK strategies, combination approaches and emerging precision-delivery or targeted-degradation concepts. Available clinical data remain limited compared with the extensive preclinical literature, supporting biomarker-driven rather than indiscriminate NF-κB inhibition. The review identifies the major translational gaps and proposes a framework for subtype- and context-selective NF-κB targeting.