The beneficial effect of dietary soy food intake, especially for women diagnosed with
breast cancer, is controversial, as in vitro data has shown that the soy
isoflavones genistein and
daidzein may even stimulate the proliferation of
estrogen-receptor alpha positive (ERα+)
breast cancer cells at low concentrations. As
genistein and
daidzein are known to inhibit key
enzymes in the
steroid metabolism pathway, and thus may influence levels of active
estrogens, we investigated the impacts of
genistein and
daidzein on the formation of
estrogen metabolites, namely 17β-estradiol (E2), 17β-estradiol-3-(β-D-glucuronide) (E2-G), 17β-estradiol-3-sulfate (E2-S) and
estrone-3-sulfate (E1-S) in
estrogen-dependent ERα+ MCF-7 cells. We found that both
isoflavones were potent inhibitors of E1 and E2 sulfation (85-95% inhibition
at 10 μM), but impeded E2 glucuronidation to a lesser extent (55-60% inhibition
at 10 μM). The stronger inhibition of E1 and E2 sulfation compared with E2 glucuronidation was more evident for
genistein, as indicated by significantly lower inhibition constants for
genistein [Kis: E2-S (0.32 μM) < E1-S (0.76 μM) < E2-G (6.01 μM)] when compared with those for
daidzein [Kis: E2-S (0.48 μM) < E1-S (1.64 μM) < E2-G (7.31 μM)]. Concomitant with the suppression of E1 and E2 conjugation, we observed a minor but statistically significant increase in E2 concentration of approximately 20%. As the content of
genistein and
daidzein in soy food is relatively low, an increased risk of
breast cancer development and progression in women may only be observed following consumption of high-dose
isoflavone supplements. Further long-term human studies monitoring free
estrogens and their conjugates are therefore highly warranted to evaluate the potential side effects of high-dose
genistein and
daidzein, especially in patients diagnosed with ERα+
breast cancer.