Flavonol-mediated modulation of angiogenesis-related microRNAs in breast cancer : a narrative synthesis of current evidence and knowledge gaps

Abstract

Angiogenesis is essential for breast cancer progression and metastasis; however, the clinical impact of vascular endothelial growth factor (VEGF)-targeted therapies remains limited due to adaptive resistance and activation of compensatory angiogenic pathways. Angiogenesis-regulating microRNAs (angiomiRs) act as upstream modulators of both VEGF-dependent and VEGF-independent signaling networks contributing to vascular plasticity, immune evasion, and therapeutic escape. Dietary flavonols such as kaempferol, myricetin, and quercetin have demonstrated anti-angiogenic activity in preclinical models, yet their mechanistic interaction with angiomiR-mediated regulation in breast cancer remains poorly characterized. This narrative review critically evaluates evidence identified through structured searches of Google Scholar, PubMed, Scopus, and Web of Science (2010–2026). We synthesize mechanistic and translational findings linking flavonols to microRNA-associated regulation of hypoxia signaling, endothelial activation, extracellular vesicle communication, and vascular normalization. Available evidence indicates that flavonols may influence angiogenic pathways both directly, by inhibiting key signaling cascades, and indirectly, through modulation of non-coding RNA networks. Despite these insights, experimental validation of specific flavonol-angiomiR interactions in breast cancer remains limited. AngiomiR modulation by flavonols, therefore, represents a mechanistically grounded but predominantly preclinical concept that warrants further translational investigation to clarify its therapeutic relevance and potential applications within precision oncology in breast cancer.

PLAIN LANGUAGE SUMMARY : Blood vessels are essential for supplying breast cancer tumors with nutrients and oxygen. Tumors often rely on a molecule called vascular endothelial growth factor (VEGF) to form new blood vessels. For this reason, treatments that block VEGF have been developed to slow tumor growth. However, these treatments can lose effectiveness over time because cancer cells can find alternative ways to keep their blood supply. Blood vessel formation is controlled by signals within cells. MicroRNAs (miRNAs) are very small molecules that help turn genes on or off, influencing how blood vessels develop and how tumors respond to treatment. Flavonols are naturally occurring compounds found in certain fruits and vegetables. Some studies suggest that flavonols can affect blood vessel growth, possibly by influencing miRNAs involved in this process. Although early findings are promising, most evidence comes from laboratory and preclinical studies. Further research is needed to determine whether targeting these pathways could lead to safe and effective treatment strategies for patients with breast cancer.