The Role of EGFR in Triple-Negative and Basal-Like Breast Cancer: Signalling Mechanisms and Drug Resistance

Breast cancer remains the most prevalent cancer among women globally, with aggressive subtypes such as triple-negative breast cancer (TNBC) posing significant therapeutic challenges. The Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase, is a pivotal driver in these cancers through its roles in cell proliferation, survival, and metastasis. EGFR’s structure includes extracellular ligand-binding and intracellular kinase domains that activate multiple oncogenic pathways, chiefly MAPK and PI3K/AKT. Dysregulation in breast cancer occurs via overexpression, activating mutations, and autocrine loops, predominantly in TNBC and basal-like subtypes, correlating with poor prognosis. Therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors have met limited success, often hindered by tumour heterogeneity and resistance mechanisms. Multi-omics and pathway analyses affirm EGFR’s role as a central signalling hub intertwined with critical pathways such as MAPK/ERK and PI3K/AKT/mTOR, and reveal metabolic and phosphorylation signatures highlighting its functional activity. Genetic evidence reflects modest yet significant breast cancer risk associations with predominantly missense variants. Challenges remain in biomarker refinement and overcoming resistance, emphasising combination therapies and novel inhibitors as future directions. This integrated analysis underscores EGFR’s continued promise as a therapeutic target in breast cancer, especially for aggressive subtypes lacking effective treatment options.