Phytoestrogens have attracted attention as being safer alternatives to
hormone replacement therapy (HRT) and as chemopreventive
reagents for
breast cancer because dietary soy
isoflavone intake has been correlated with reduction in risk. To identify safe and effective
phytoestrogen candidates for HRT and
breast cancer prevention, we investigated the effects of
daidzein,
genistein,
coumestrol,
resveratrol and
glycitein on cell growth, cell cycle,
cyclin D1 expression, apoptosis, Bcl-2/Bax expression ratio and p53-dependent or
NF-kappaB-dependent transcriptional activity in MCF-7
breast cancer cells.
Phytoestrogens, except for
glycitein, significantly enhanced
estrogen-response-element-dependent transcriptional activity up to a level similar to that of 17beta-estradiol (E(2)). E(2) increased cell growth significantly,
coumestrol increased cell growth moderately, and
resveratrol and
glycitein reduced cell growth.
Phytoestrogens, except for
glycitein, stimulated the promotion of cells to G(1)/S transition in cell cycle analysis, similar to E(2). This stimulation was accompanied by transient up-regulation of
cyclin D1. While
genistein,
resveratrol and
glycitein all increased apoptosis and reduced the Bcl-2/Bax ratio,
resveratrol reduced this ratio more than either
genistein or
glycitein. Moreover,
resveratrol significantly enhanced p53-dependent transcriptional activity, but slightly reduced
NF-kappaB-dependent transcriptional activity. On knockdown analysis,
genistein,
resveratrol and
glycitein all reduced the Bcl-2/Bax ratio in the presence of apoptosis-inducing stimuli, and
estrogen receptor (ER) alpha silencing had no effect on these reductions. In contrast, in the absence of apoptosis-inducing stimuli, only
resveratrol reduced the ratio, and
ERalpha silencing abolished this reduction. Thus,
resveratrol might be the most promising candidate for HRT and
chemoprevention of
breast cancer due to its estrogenic activity and high antitumor activity.