NUTRITIONAL FLAVONOIDS MODULATE ESTROGEN RECEPTORS SIGNALING

Estrogen receptors (ER and ER mediate 17-estradiol (E2) actions through the transcription of E2-sensitive target genes. In addition, rapid non-genomic signaling (e.g., MAPK/ERK, PI3K/AKT) occurs. It is now well accepted that these rapid membrane-initiated responses account for E2-related proliferation. Beside many beneficial effects on human health, nutritional flavonoids exert protective and antimitogenic effects on E2-related proliferation. The mechanism(s) underlying these effects seems to be related to flavonoids antioxidant properties and/or to their ability to alter signal transduction protein kinases. In addition, an antiestrogenic activity has been proposed but not yet defined. However, the identification and characterization of the responsible mechanisms for flavonoid antitumoral effects is poorly understood. Here, we investigated the possibility that the antimitogenic effects of flavonoids are transduced by modulating ERs-mediated rapid signaling. The ability of two flavonoids, the flavanone naringenin and the flavanol quercetin, abundant in Mediterranean diet, to induce ERs activities has been studied with respect of E2. Our results indicate that flavonoids act as E2 mimetic on ER transcriptional activity, whereas they impair the activation of rapid signalling pathways committed to E2-induced proliferation. The resulting decoupling of ER signal transduction could be proposed as a new mechanism in the protective effects of flavonoids against E2-related proliferation