Flavonoids as Anti-Metastatic Agents: Targeting the Epithelial-Mesenchymal Transition (EMT) in Breast Cancer Treatment: Flavonoids as Anti-Metastatic Agents

Breast cancer locoregional invasion and metastasis are the main reasons for patient mortality, being driven by the malignant tumor cell development. One of the main processes of their formation is the epithelial–mesenchymal transition (EMT), initially described in embryonic development, during which it facilitates cell migration and differentiation. In breast cancer, EMT is a key process mediating metastasis, therapeutic resistance, and cancer stem cell renewal. Flavonoids, a broad class of naturally derived polyphenols known for their strong antioxidant and anti-inflammatory effects, have attracted considerable interest because of their promising therapeutic applications in breast cancer. Extensive in vitro and in vivo studies demonstrate that flavonoids modulate EMT by inhibiting key regulatory molecules such as TWIST1, CD44, SNAI1/2, N-cadherin, ZEB1, integrins, matrix metalloproteinases (MMPs), and vimentin, while upregulating the epithelial marker E-cadherin. These effects are mediated through the suppression of pivotal oncogenic signaling pathways, such as NF-κB p65, PI3K/AKT, and JAK2/STAT3, which are critically involved in breast cancer progression. EMT is also regulated by some families of transcription factors, notably the Zn-finger family (e.g., ZEB1, ZEB2, SNAI2), which suppress E-cadherin transcription by binding to E-boxes. Given their multitargeted mechanism of action and ability to disrupt EMT processes specifically in breast cancer, flavonoids represent promising candidates for anti-metastatic therapy. This review summarizes the mechanistic roles of flavonoids in EMT suppression within the context of breast cancer and explores their translational relevance as adjuncts in targeted breast cancer therapy. Incorporating flavonoid-based strategies may improve therapeutic outcomes in aggressive breast cancer subtypes by mitigating metastatic progression and enhancing patient prognosis.