Genistein and daidzein should be avoided for breast cancer
Soybeans are a major dietary source of the isoflavones genistein and daidzein. Both are phytoestrogens, plant molecules that are structurally and functionally similar to mammalian estrogens. Phytoestrogens are thought possibly to inhibit binding of the more potent endogenous estrogens and decrease their potential effects on breast cancer risk by competing for estrogen receptors. On the other hand, phytoestrogens appear to be capable of promoting estrogen positive breast cancer under some circumstances. Genistein accounts for approximately 50% of total soy isoflavones, whereas daidzein accounts for about 40%. Genistein is also a component of currants, parsley and sage, as well as other legumes such as chickpeas. Daidzein is also found in currants and some other legumes such as fava beans. This article covers genistein and daidzein in general. The recommendation above refers to genistein and daidzein supplements, not isoflavones as found in food.
Genistein has been shown to have antiviral and antioxidant properties, and has been shown to ameliorate fatty liver in insulin resistant rats. Like estrogen, soy phytoestrogens are have been shown to have neuroprotective actions, however, unlike estrogen, genistein and daidzein have been shown to be toxic to primary neuronal culture at high concentrations.
The major isoflavones in soybeans are actually genistin and daidzin, the glycoside conjugates of genistein and daidzein. Genistin and daidzin are converted by human gut bacterial flora into genistein and daidzein and other compounds such as O-desmethylangolensin (ODMA), 5-hydroxy-equol (from genistin), and equol (from daidzin). Equol has been shown to have the strongest binding affinities and estrogenic activities (especially for ERβ) among the daidzin metabolites and has been hypothesized to be largely responsible for the estrogen-like activities of soy and its isoflavones. However, there is a great deal of variation among individuals in the metabolism of genistin and daidzin, which appears to be dependent partly on environmental factors, including other components of the diet, and partly on genetic factors.
Only 25% to 35% of the U.S. Caucasian population is capable of converting daidzein to equol, whereas people in high soy consumption areas of Asia have rates closer to 40% to 60%. There is some evidence that Hispanic or Latino women are also more likely to be equol producers. Approximately 80% to 90% of people harbor the bacteria required to produce ODMA. The frequency of equol producers in one study of vegetarians was found to be 59%, similar to the reported frequency in Japanese adults consuming soy, and much higher than for nonvegetarian adults (25%). One Japanese study found that consumption of dairy products was significantly higher in those who did not excrete equol than in those who did. Seaweed consumption has been found to enhance intestinal production of equol, which could partially explain some of the breast cancer protective effects of Asian diets that are high in both seaweed and soy. Another U.S. study comparing Korean American and Caucasian American women and girls found that the prevalence of equol-producers was higher (51% vs. 36%) and the prevalence of ODMA-producers was lower (84% vs. 92%) in the Korean Americans.
The differences in rates of equol producers partially explains the generally tepid effects found for soy consumption in studies of European and U.S. populations compared to Asian populations. It makes sense that Asian populations, which have had many thousands of years to develop their ability to digest and extract nutrients from soybeans (which are less digestible than most other commonly-consumed foods), would have a slightly different genetic profile than populations that are relatively new to soy consumption. Laboratory animal species used in breast cancer studies tend to produce high levels of equol, which means that animal studies may overestimate the effects of consuming soy or soy isoflavones in women.
Breast cancer-related effects of consuming genistein and daidzein
Our conclusions about the effects of consuming genistein and daidzein supplements are based on three types of information: (1) studies of the impact of genistein, daidzein or equol on breast cancer cells; (2) studies of the effect of consuming genistein or daidzein or diets rich in these phytoestrogens on breast cancer in animals; and (3) human studies and observations. Laboratory studies on breast cancer cell lines shed light on the possible mechanism of action of these compounds, but they do not necessarily provide convincing evidence of similar actions in women, especially since the results appear to be contradictory. Animal studies also provide important information because they have been performed in a controlled environment with well defined conditions, however, they again cannot reliably model the effects of soy phytoestrogens, especially since the reaction to these compounds differs among women depending on their genetic makeup. Finally, human experiments with well-defined soy-related dietary inputs can provide meaningful information on the relationship between soy phytoestrogen consumption and breast cancer risk, but they are subject to multiple confounding factors and genetic differences between women. Below, we summarize the results of the three types of studies. Note that population studies relating to soy food consumption are found in the soybeans, tofu, soybean paste, soy protein isolate, and soybean oil web pages.
Breast cancer cell (in vitro) studies
Studies of the impact of genistein, daidzein or equol on breast cancer cells have found the following:
- A study designed to evaluate the effects of low-dose, long-term genistein exposure on (ER+/PR+) MCF-7 breast cancer cells was performed by culturing the cells in genistein for 10-12 weeks. It was found that the treatment significantly reduced the growth promoting effects of estradiol (E2) and resulted in a down-regulation of the PI3-K/Akt signaling pathway (a mechanism through which genistein might offer protection against breast cancer). However, it did not result in decreased expression of estrogen receptor alpha (ERα).
- Another study found that genistein can induce (ER+/PR+) human MCF-7 breast cancer cell growth. In addition, genistein was found to increase breast cancer-associated aromatase activity in such cells and to negate the growth inhibitory action of an aromatase inhibitor at physiologically relevant concentrations.
- A study examining the mechanism by which genistein can trigger G2/M cell cycle arrest and inhibit cell growth in (triple negative) MDA-MB-231 breast cancer cells found that the Ras/MAPK/AP-1 signal pathway might be involved.
- A study designed to determine whether soy genistein has a genotoxic effect on normal breast cancer cells at low-dose, physiological concentrations found that after three months of exposure, the cells evinced loss of a normal chromosome 8, gain of an extra chromosome 20, and loss of a chromosomal segment of chromosome 9, leading to the homozygous deletion of the two tumor suppressor genes CDKN2A (p16INK4a) and CDKN2B (p15INK4b). The authors comment that these genotoxic effects may contribute to soy- and genistein-associated breast cancer risk.
- A study designed to examine mechanisms by which daidzein inhibits the growth of breast cancer cells found that daidzein significantly inhibited MCF-7 and (fibroblast growth factor receptor overexpressing) MDA-MB-453 breast cancer cell proliferation in a dose- and time-dependent manner. Further testing found that daidzein exerted its anticancer effects via cell cycle arrest at the G1 and G2/M phases.
- A study designed to examine gene expression patterns in MCF-7 breast cancer cells at both physiologic (1 or 5 μM) and pharmacologic (25 μM) genistein concentrations found that genistein modified the expression of genes belonging to multiple pathways, including estrogen- and p53-mediated pathways. At physiologic concentrations, genistein induced expression suggestive of increased proliferation, while at pharmacologic concentration, genistein induced expression suggestive of increased apoptosis, decreased proliferation and decreased total cell number.
- A study found that caffeine enhanced the inhibition of cell proliferation induced by genistein in the hormone-independent breast cancer cell line MDA-MB-435S. Genistein induced a concentration-dependent accumulation of cells in the G2/M phase of the cell cycle which caffeine reversed. The authors comment that this reversal by caffeine of genistein-induced G2/M phase could enhance genistein-induced inhibition of cell growth.
- A study focusing on the effects of equol in human breast cancer cells found that equol significantly inhibited proliferation in MDA-MB-453 cells in a dose- and time-dependent manner. However, equol stimulated proliferation in MCF-7 cells at low concentrations (<1 ÁM) and only inhibited proliferation at a high concentration (100 ÁM). During equol-induced apoptosis, equol increased the number of cells in the sub-G0 phase and enhanced the level of p53, leading the authors to conclude that equol-induced cell cycle arrest and apoptosis involves a p53-dependent pathway.
- In another study, phytoestrogens extracted from soymilk were used to treat human target cells that represent a common model system for mammary tumorigenesis. The soy phytoestrogens were found to induce a genomic fingerprint indistinguishable from the transcriptional effects of 17β-estradiol. More diverging transcriptional profiles were generated when steps were taken to reconstitute the expression of estrogen receptor β (ERβ). The authors conclude that soy phytoestrogens appear to mitigate estrogenic signaling in the presence of both estrogen receptor subtypes but, in late-stage cancer cells lacking ERβ, these phytochemicals contribute to a tumor-promoting transcriptional signature.
- A study designed to examine whether certain carotenoids (lycopene, phytoene, phytofluene, and beta-carotene) can inhibit signaling of phytoestrogens found that treatment of MCF-7 and (ERα-positive) T47D breast cancer cells with genistein induced cell proliferation, cell-cycle progression and transactivation of the estrogen response element, actions similar to the known effects of 17β-estradiol in promoting breast cancer. Each of the carotenoids tested reduced proliferation induced by 17β-estradiol and genistein, thereby potentially reducing their harmful effect in hormone-dependent cancers.
- A study designed to evaluate the impact of the combination of genistein and indole-3-carbinol (found in broccoli and other brassica vegetables) on MCF-7 breast cancer cells found a synergistic effect of genistein and I3C in increasing apoptosis and decreasing ER-α expression.
- A study found that genistein induced aromatase activity in liver cells. After menopause, when the ovaries stop producing the hormone, localized estrogen synthesis in other tissues become more significant physiologically. The study illustrated an extragonadal pathway by which genistein might increase estrogen synthesis.
- A study found that genistein induced increased cellular proliferation and tamoxifen resistance in hormone receptor positive HER2/neu overexpressing (HER2+) cells.
Bottom line: Soy phytoestrogens have been shown both to inhibit and to promote breast cancer cell growth in the laboratory, depending on the concentrations and numerous other factors (such as whether they are administered in the presence of caffeine, certain carotenoids, or indole-3-carbinol (found in brassica vegetables)). The evidence hints that the potential for breast cancer promotion may be greater in later stages of breast cancer.
Animal (in vivo) studies
Studies of the impact of genistein, daidzein or equol in animal breast cancer models have found the following:
- A study using a post-menopausal rat model with carcinogen-induced mammary tumors found that soy phytoestrogen extract inhibited proliferation, induced apoptosis, and inhibited angiogenesis. Furthermore, the extract was found to have better antitumor effects than single soy phytoestrogens.
- A study designed to evaluate whether dietary genistein interacts with tamoxifen therapy was performed by implanting estrogen-dependent tumors into ovariectomized mice and administering estradiol, estradiol plus tamoxifen, or estradiol plus tamoxifen plus dietary genistein. It was found that dietary genistein was able to negate the inhibitory effect of tamoxifen on estrogen-stimulated tumor growth.
- A study designed to examine the interaction of dietary genistein and the aromatase inhibitor Femara on the growth of mammary tumors in a mouse model found that genistein increased the growth of mammary tumors implanted in ovariectomized mice and negated the inhibitory effect of Femara on tumor growth. The authors note that the findings are significant because tumors that express aromatase and synthesize estrogen are good candidates for aromatase inhibitor therapy.
- A study designed to investigate the impact of genistein and daidzein with respect to metastatic breast cancer in mice found that genistein significantly decreased primary mammary growth while daidzein increased primary mammary growth. Similarly, genistein was shown to decrease metastasis to distant sites while daidzein increased the number of metastases compared to a control group. The authors conclude that genistein can be used as an effective breast cancer metastasis preventive but consumption of soy foods that also contain daidzein may not be safe.
- Another study examining the impact of soy isoflavones during treatment with tamoxifen using a tamoxifen-resistant tumor model that exhibits autonomous growth and estradiol-induced tumor regression. Coadministration of tamoxifen with either daidzein or genistein was found to produce tumors of greater size than with tamoxifen alone. The authors conclude that simultaneous consumption of isoflavone supplements with tamoxifen may not be safe.
- A study using a mouse model found that exposure to environmentally relevant doses of genistein caused deleterious effects on the developing female reproductive system. Ovarian function and estrous cyclicity were disrupted by neonatal exposure to genistein. Reduced fertility was also observed in mice treated with genistein. In addition, female offspring of genistein treated females (bred to control males) also exhibited altered ovarian differentiation. The authors comment that whether adverse effects occur in human infants exposed to soy infant formula is unknown.
- A study using a mouse model found that consumption of a combination of flaxseed and soy, or their phytoestrogens, reduced the tumor growth stimulatory effect of soy or genistein. The authors conclude that if soy is consumed with lignan-rich foods, it might continue to induce its other beneficial health effects, without inducing adverse effect on postmenopausal breast cancer.
- A study of the effects of dietary daidzein and equol on estrogen-dependent human breast cancer found that while both daidzein and equol had proliferative effects on MCF-7 cell growth at physiological concentrations in vitro and dietary daidzein had a slight but significant stimulatory effect on tumor growth in vivo (i.e., in tumors implanted in ovariectomized mice), equol did not stimulate the growth of estrogen-dependent breast tumor growth in mice. Nor did equol increase tumor cell proliferation. These results suggest that the estrogenic effects of daidzein and equol are attenuated in the body.
Human experiments and studies
Below is a summary of selected studies of the impact of genistein, daidzein or equol on breast cancer in human experiments and other studies. Note that studies of dietary soy food intake and breast cancer risk are found in our various soy foods web pages.
- A prospective study of Japanese women found that a high level of genistein in the blood (but not daidzein and not dietary consumption of isoflavones) was associated with lower risk of breast cancer.
- A prospective study of European women found no protective effect for high levels of genistein and other phytoestrogens in the blood and urine against breast cancer. The risk of breast cancer was found to be increased slightly with higher levels of urinary equol for those with estrogen receptor-positive (ER+) breast cancer.
- A U.S. study of the relationship between soy intake and mammographic breast density in postmenopausal women found that among equol producers, those with weekly soy intake had lower percent density, whereas among nonproducers, weekly soy intake was associated with higher breast density.
- A Chinese study found that plasma genistein and daidzein concentrations were inversely associated both with benign fibrocystic breast disease and with breast cancer, suggesting that the protective effects of soy isoflavones on cancer risk occur early in carcinogenesis in this population.
- A prospective study in a Dutch population designed to examine the association between plasma levels of isoflavones (daidzein, genistein, glycitein, O-desmethylangolensin, and equol) and lignans (enterodiol and enterolactone) and breast cancer risk found that high circulating genistein levels were associated with reduced breast cancer risk. The results did not differ by menopausal status. Lignan levels were not found to be associated with breast cancer risk.
- A German case control study found that while premenopausal breast cancer risk was found to decrease with increasing plasma enterolactone concentrations, there was no significant association found between plasma genistein concentration and premenopausal breast cancer risk.
- A male breast cancer case has been reported whose history included extensive use of supplemental phytoestrogens and the absence of any family history of breast cancer or BRCA1/BRCA2 mutation. Another case has been reported of a 39-year-old woman diagnosed with cancer of the endometrium whose medical history was also notable for extensive use of supplemental phytoestrogens. The phytoestrogens appeared to act on the endometrium in a similar fashion to unopposed estrogen.
- A year-long double-blind Netherlands trial designed to test soy supplementation as a substitute for postmenopausal estrogen therapy found that the use of soy protein supplement containing specified levels isoflavones did not improve cognitive function, bone mineral density, or plasma lipids in healthy postmenopausal women when started at the age of 60 years or later. Another study found that supplementation with pure soy isoflavonoids did not alleviate menopausal symptoms in breast cancer patients.
- A United Kingdom prospective study designed to evaluate the association between serum and urine levels of seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) and breast cancer risk found that exposure to all isoflavones was associated with increased risk of breast cancer, significantly so for equol and daidzein.
- A German case-control study of dietary phytoestrogen intake among premenopausal breast cancer cases found that daidzein and genistein had protective effects, but only for hormone receptor-positive tumors. Intake of the mammalian lignans, enterodiol and enterolactone, were inversely associated with breast cancer risk. No effect was found for overall total phytoestrogen intake.
- A small Korean study reported that soybean and soy isoflavone consumption was found to be associated with increased risk of recurrence among women with HER2/neu overexpressing (HER2+) tumors, whereas it reduced risk of relapse in women with HER2- disease.
Asian studies are more likely than European or U.S. studies to find an association between soy isoflavonoid consumption and reduced breast cancer risk. In fact, some non-Asian studies have found a slightly increased risk of breast cancer for total phytoestrogen consumption or individual phytoestrogens, including equol.
Isoflavone supplements should be avoided
Based on the available evidence, consuming genistein, daidzein or equol supplements might promote breast cancer growth under some conditions, especially in breast cancer survivors, and consuming them appears inadvisable.angiogenesis, aromataseActivity, aromataseInhibitors, BRCA1BRCA2, daidzein, endometrialCancer, enterolactone, equol, estradiol, Femara, genistein, Her2Overexpressing, I3C, infantFormula, insulinResistance, isoflavones, letrozole, lignan, phytoestrogens, proliferation, soybean, soybeanPaste, soyProteinIsolate, tamoxifen, tamoxifenResistant, tofu