Targeting Receptor Tyrosine Kinase–Driven Drug Resistance in Breast Cancer Using Dietary Polyphenols: Molecular Crosstalk Between EGFR, HER2, VEGFR2, and Downstream Survival Pathways

Abstract

Breast cancer progression and therapeutic resistance are strongly influenced by aberrant receptor tyrosine kinase (RTK)–mediated signaling transduction, particularly involving epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), and vascular endothelial growth factor receptor-2 (VEGFR2). Although RTK-targeted therapies have significantly improved patient outcomes, their long-term efficacy is frequently compromised by adaptive resistance arising from receptor crosstalk, pathway redundancy, and downstream survival signaling. Increasing attention has therefore been directed toward multitarget strategies capable of disrupting RTK signaling networks rather than individual receptors. Naturally occurring dietary polyphenols have emerged as promising candidates in this context due to their pleiotropic molecular actions, favorable safety profiles, and ability to modulate multiple oncogenic pathways simultaneously. Accumulating in-vitro and in-vivo evidence indicates that polyphenol combinations can inhibit RTK activation, suppress PI3K/AKT/mTOR and MAPK/ERK signaling, attenuate angiogenesis, reverse multidrug resistance, and promote apoptosis in breast cancer models. This review systematically examines the molecular crosstalk among EGFR, HER2, and VEGFR2 in breast cancer progression and resistance, and critically evaluates the mechanistic basis by which polyphenol combinations interfere with RTK-driven signaling transduction. Emphasis is placed on translational insights derived from experimental studies and the potential integration of polyphenol-based strategies into future precision oncology frameworks.