Abstract
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.
Highlights
Breast cancer is the most prevalent cancer in women and the second leading cause of cancer-related deaths among females worldwide (Ferlay et al, 2015)
In ER alpha negative (ERα−) cells (MDA-MB-231), this biphasic effect is not observed; both phytoestrogens exhibit an anti-proliferative effect only. This indicates that the proliferative effect of genistein and daidzein, as observed at low doses, is estrogen receptor alpha (ERα)-mediated, while estrogen receptor beta (ERβ), which is expressed at low levels in both MCF-7 and MDA-MB-231 cells, seems to oppose ERα actions and exhibits anti-migratory and anti-invasive properties (Vladusic et al, 2000; Al-Bader et al, 2011; Wang et al, 2012; Uifãlean et al, 2016)
Concomitant with the observed suppression of SULT- and UDP-glucuronosyl transferase (UGT)-mediated conjugation of E1 and E2, we observed a minor but statistically significant increase in E2 formation (Figure 5)
Summary
Breast cancer is the most prevalent cancer in women and the second leading cause of cancer-related deaths among females worldwide (Ferlay et al, 2015). Evidence from epidemiological and experimental studies indicates that several natural products may act as chemopreventive agents and inhibit mammary carcinogenesis (Pan et al, 2015). Among these products is soy, which contains variable amounts of genistein and daidzein as the major isoflavones (approximately 47 and 44%, respectively) and minor amounts of glycitein (approximately 9% of the total isoflavones in soybeans). In vitro studies have shown that both genistein and daidzein stimulate the proliferation of MCF-7 human estrogen-receptor alpha positive (ERα+) breast cancer cells at low concentrations, but inhibit tumor growth at higher doses. This indicates that the proliferative effect of genistein and daidzein, as observed at low doses, is ERα-mediated, while ERβ, which is expressed at low levels in both MCF-7 and MDA-MB-231 cells, seems to oppose ERα actions and exhibits anti-migratory and anti-invasive properties (Vladusic et al, 2000; Al-Bader et al, 2011; Wang et al, 2012; Uifãlean et al, 2016)
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