Opportunities, obstacles and current challenges of flavonoids for luminal and triple-negative breast cancer therapy

Flavonoids are a large group of polyphenols with numerous biological effects on cancer cells. They have been shown to affect proliferation via cell cycle arrest, apoptosis and necrosis and to exert anti-oxidant, anti-inflammatory and anti-mutagenic actions. Anti-cancer effects of flavonoids, mostly in preclinical evaluations, should be translated into clinical cancer treatment research, where evidence is still scarce. Although therapies targeting primary breast tumors have markedly improved, those targeting elusive micro-metastases are less effective. In this scenario, the present review discusses the anti-tumor effects of different simple natural and synthetic flavonoids on luminal and triple-negative breast cancer, highlighting biological effects such as apoptosis, epithelial-mesenchymal transition reversion, cell migration and invasion inhibition, metalloprotease inactivation/down-regulation and anti-angiogenesis, as well as compiling in vivo treatments in experimental tumor models and some specific clinical trials. In addition, this review discusses the mechanisms underlying flavonoid anti-tumor effects. Moreover, although flavonoids may be regarded as a spectrum of promising polyphenols with multifaceted anti-tumor effects, mainly applicable to metastatic breast cancer management, some major challenges and concerns about potential flavonoid therapy in luminal and triple-negative breast cancer are also discussed.