The stimulation of cell proliferation by quercetin is mediated by the estrogen receptor

Quercetin causes biphasic modulation of the proliferation of specific colon and mammary cancer cells. In this study, the possible involvement of the estrogen receptor (ER) in the stimulation of cell proliferation by quercetin was investigated. For this purpose, the effect of quercetin on cell proliferation was tested in ER-positive MCF-7 and T47D cells, and in ER-negative HCC-38 and MDA-MB231 cells. Quercetin stimulated proliferation of ER-positive cells only, suggesting this effect to be ER-dependent. In support of these results, quercetin induced ER-ERE-mediated gene expression in a reporter gene assay using U2-OS cells transfected with either ERalpha or ERbeta, with 10(5)-10(6) times lower affinity than 17beta-estradiol (E2) and 10(2)-10(3 )times lower affinity than genistein. Quercetin activated the ERbeta to a 4.5-fold higher level than E2, whereas the maximum induction level of ERalpha by quercetin was only 1.7 fold that of E2. These results point at the relatively high capacity of quercetin to stimulate supposed 'beneficial' ERbeta responses as compared to the stimulation of ERalpha, the receptor possibly involved in adverse cell proliferative effects. Altogether, the results of this study reveal that physiologically relevant concentrations of quercetin can exert phytoestrogen-like activity similar to that observed for the isoflavonoid genistein.