The Journal of Nutrition
Supplement: Soy Summit—Exploration of the Nutrition and Health Effects of Whole Soy
Is Soy Consumption Good or Bad for
Leena Hilakivi-Clarke,4,5* Juan E. Andrade,6and William Helferich6
4Lombardi Comprehensive Cancer Center and5Department of Oncology, Georgetown University, Washington, DC 20057; and
6Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, IL 61801
Genistein in soy activates estrogen receptor (ER)-a and ERb and acts as an estradiol in multiple target tissues. Because
estrogens increase breast cancer risk and genistein promotes the growth of ER-positive human breast cancer cells, it has
remained unclear whetherthis isoflavone or soy is safe. Resultsreviewed here suggest that women consuming moderate
amounts of soy throughout their life have lower breast cancer risk than women who do not consume soy; however, this
protectiveeffect may originate from soy intake early in life. We also review the literature regarding potential risks genistein
poses for breast cancer survivors. Findings obtained in 2 recent human studies show that a moderate consumption of diet
containing this isoflavone does not increase the risk of breast cancer recurrence in Western women, and Asian breast
cancer survivors exhibit better prognosis if they continue consuming a soy diet. The mechanisms explaining the breast
cancer risk-reducing effect of early soy intake or the protective effect in Asian breast cancer survivors remain to be
established. We propose that the reduction in risk involves epigenetic changes that result in alterations in the expression
of genes that regulate mammary epithelial cell fate, i.e. cell proliferation and differentiation. Lifetime soy consumption at a
moderate level may prevent breast cancer recurrence through mechanisms that change the biology of tumors; e.g.
women who consumed soy during childhood develop breast cancers that express significantly reduced Human epidermal
growth factor receptor 2 levels. More research is needed to understand why soy intake during early life may both reduce
breast cancer risk and risk of recurrence.J. Nutr. 140: 2326S–2334S, 2010.
Breast cancer is strongly associated with estrogens. Ovarian es-
trogens, adipose-derived estrogens, and estrogenic compounds,
e.g. in the diet, promote the growth of estrogen receptor (ER)7
positive (ER+) breast cancer cells in vitro and in vivo in athymic
mice (1). In addition, estrogens and estrogenic compounds
promote the growth of rodent ER+ mammary tumors (2). In
humans, lifetime exposure to high estrogen levels is associated
with increased breast cancer risk (3). For these reasons, estrogens
present in our food and environment may pose a risk to humans.
Isoflavones are known to accumulate in many plant species at
various concentrations. Dietary legumes such as black beans,
lentils, lima beans, Mung beans, and soybeans are sources of a
and derivates is widely available in Western diets, such as oil,
meal, flour, protein isolates, and dairy and meat substitutes,
including milk,yogurt, icecream, cheese, sausages, and“veggie”
1Published in a supplement to The Journal of Nutrition. Presented at the
conference, “Soy Summit: Exploration of the Nutrition and Health Effects of
Whole Soy,” held in New York, NY, September 21–22, 2009. The conference
was organized by the Institute of Human Nutrition, Columbia University, through
an unrestricted educational grant from Pharmavite, LLC. The supplement
coordinators for this supplement are Sharon R. Akabas, Columbia University,
and Connie M. Weaver, Purdue University. Supplement Coordinator disclosure:
S. Akabas and C. Weaver received travel costs and an honorarium from a
nonrestricted educational grant provided by Pharmavite LLC to Columbia
University for the Soy Summit, which served as the basis for this supplement.
The grant provided funding for the summit and also covered the cost of this
journal supplement. Connie M. Weaver serves on Pharmavite’s Advisory Board.
The Guest Editor for this supplement is Neil Shay. Guest Editor Disclosure: Neil
Shay declares no conflict of interest. The supplement is the responsibility of the
guest editors to whom the Editor of The Journal of Nutrition has delegated
supervision of both technical conformity to the published regulations of The
Journal of Nutrition and general oversight of the scientific merit of each article.
Publication costs for this supplement were defrayed in part by the payment of
page charges. This publication must therefore be hereby marked "advertisement"
in accordance with 18 USC section 1734 solely to indicate this fact. The opinions
expressed inthis publication are those ofthe authors and are not attributable to the
sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition.
* To whom correspondence should be addressed. E-mail: clarkel@georgetown.
2Supported by the National Cancer Institute (U54 CA000970 to L.H-C.), the
National Institute on Aging (P01 AG024387 to W.G.H.), the National Institute for
Complementary and Alternative Medicine, the Office of Dietary Supplements,
and the Women’s Health Initiative.
3Author disclosures: L. Hilakivi-Clarke and W. Helferich received travel costs and
L. Hilakivi-Clarke, J. E. Andrade, and W. Helferich received an honorarium from a
nonrestricted educational grant provided by Pharmavite LLC to Columbia
University for the Soy Summit, which served as the basis for this article. The
grant provided funding for the summit and also covered the cost of this journal
7Abbreviations used: E2, estradiol; EGFR, epidermal growth factor receptor; ER,
estrogen receptor; ERE, estrogen response element; Her2, human epidermal
growth factor receptor 2; OR, odds ratio.
ã 2010 American Society for Nutrition.
First published online October 27, 2010; doi:10.3945/jn.110.124230.
burgers. Many of these contain several-fold more isoflavones
soy foods in the Western markets, soy food consumption is still
high exposure to soy and isoflavones (7). For example, consump-
tion is significantly different even in Chinese Americans (4 g/d)
compared with their counterparts from China (36 g/d) (8). Most
of the rise in popularity of soy products, and lately of dietary
supplements containing soy isoflavones, has come from their
portrayal as the panacea for a variety of health ailments from
relieving postmenopausal symptoms (9,10) to the prevention of
cardiovascular disease (11,12) and osteoporosis (13,14). The
evidence for such health claims has been partially supportive in
some cases (15–17) and is addressed in detail in the other articles
in this issue.
The idea that soy protects against breast cancer originates
from the observation that Asian women who consume soy as a
part of their stable diet have a 3- to 5-fold lower breast cancer
risk than Caucasian women who do not regularly consume soy
(18). However, other lifestyle factors, such as degree of physical
activity, could be important contributors to explain a popula-
tion’s disparities of breast cancer incidence (19). When Asian
women immigrate to the West, their daughters who were born in
the West have higher risk than the mothers and granddaughters’
risk is similar to that of Caucasian women (20). Because Asian
American women consume significantly less soy foods than
Asian women, it is reasonable to assume that soy protects Asians
from developing breast cancer. This idea has been challenged by
the apparent estrogenicity of soy isoflavones, particularly
Estrogenicity of soy foods and genistein
Soybeans and soy foods contain several compounds with the
putative ability to inhibit carcinogenesis, including protease
inhibitors (21), phytates (22,23), and isoflavones (24–28).
Genistein has been investigated for its biological activity
related to breast cancer (29) and its estrogenic activity is well
Genistein has a very similar chemical structure to the most
potent ovarian estrogen, estradiol (E2), and consequently it
binds and activates both the ERa and ERb. The difference in
function between the 2 ER remains to be established, but it is
generally assumed that ERa mediates the proliferative actions of
estrogens and ERb binds to ERa and inhibits its action (30–32).
Although genistein binds more strongly to ERb than to ERa
(33), physiological doses of genistein activate ERa equally well
as E2 does (34). Only at very low genistein concentrations (5–8
nmol/L; in comparison, genistein concentrations in Asian
women are ~1000 nmol/L) does this isoflavone potentially act
through ERb rather than ERa (34). The actions of genistein
through the 2 ER also depend on the developmental stage of the
breast: ERb is expressed at a significantly higher level than ERa
during early development and in normal adult breast, while in
the breast tumor, ERa expression is higher than ERb expression
(35). Additional evidence for genistein binding and activating
ERa in breast tumors is that it activates a number of estrogen-
responsive genes, including pS2 and c-fos, in ER+ breast cancer
cell lines in culture (36–38).
Animal data in rodents. Findings obtained in animal studies
have further demonstrated the estrogenicity of genistein. Ovari-
ectomized rats consuming genistein at 750 mg/kg diet had higher
uterine wet and dry weights and more rapid mammary gland
growth than thecontrols. In addition, the expressionof c-fos and
pS2 in the tumors increased (37). In a similar model, dietary
genistein at 125–1000 mg/kg diet (genistein serum levels of
0.39–3.36 mmol/L) promoted the growth of estrogen-dependent
human breast cancer cells in a dose-dependent manner (39,40).
These doses parallel those observed in Asians. Using a 750-mg/kg
diet dose, Allred et al. (41) showed that genistin or its aglycone
form, genistein, stimulated the growth of human breast cancer
cells in a preclinical, postmenopausal breast cancer model (Fig.
1). Withdrawal of either isoflavone form resulted in tumor
regression. If mice were fed ,125 mg/kg diet of genistein or
genistein was administered via subcutaneous injections, the stim-
ulatory effect was not seen (26,42,43). Thus, genistein elicits
different effects in vivo depending on the dose and route of
Estrogenicity of genistein may also be modified by the matrix
it is given. Allred et al. (43) reported that consumption of
equivalent amounts of genistein from soy products at different
processing stages differently affects the proliferation of MCF-7
human breast cancer cells in ovariectomized athymic mice (Fig.
tumorregression,butthedietcontaining genistein onlydid.When
the effects of soy consumption on intact mouse mammary gland
were explored, it was found that genistein in the context of whole
soy acts as an estrogen. Specifically, Penttinen-Damdimopoulou
et al. (44) reported that consumption of whole soy activated
estrogen response element (ERE) in the mammary glands of lu-
ciferase transgenic mice. In this study, ovariectomized mice re-
ceived 160 mg/g genistein through a soy diet for 2 d, after which
there was a 6-fold increase in ERE induction in their mammary
glands compared with control-diet fed mice. Thus, dietary in-
take of whole soy activates estrogenic pathways in a mouse
mammary gland. However, this study only determined whether
(750 mg/g) stimulate growth of estrogen-dependent breast cancer
tumors MCF-7 in athymic mice. Cells (1.5 3 105MCF-7 cells/site)
were injected subcutaneously into dorsal flanks of ovariectomized
athymic mice. After tumor establishment (40 mm2), E2 pellets were
removed and mice were randomly assigned to 4 treatment groups.
Positive control (+E2) mice were reimplanted with a new E2 pellet and
along with negative controls (2E2) were fed an AIN 93G diet alone.
For phytoestrogen groups, mice consumed either dietary genistin
(1200 mg/g) or genistein (750 mg/g) mixed with AIN 93G. Tumors were
monitored weekly and tumor size was calculated and is expressed
as mean cross sectional area (mm2) of all tumors in each treatment
group 6 SEM. Data from wk 11 of treatment is presented. Figure
reproduced with permission from (41).
Equivalent amounts of dietary genistin and genistein
Soy and breast cancer2327S
ERE was activated; it did not assess changes in mammary cell
proliferation or any other functional endpoints.
Animal data in nonhuman primates. Dietary exposure
during adulthood to isoflavones does not have estrogenic effects
on nonhuman primate models. The use of a nonhuman primate
animal model is critical in reproductive biology, because the
endometrial and ovarian physiologies of monkeys are almost
identical to that of women (45). In these studies, intact or
diet containing soy or isoflavones (46,47). Uterine weight,
endometrial thickness, glandular area, and epithelial prolifera-
tion in the uterus were not significantly altered. In addition, no
evidence of estrogenic effects on the mammary gland were
observed, indicating that dietary soy isoflavones do not have
estrogenic effects on the uterus or mammary gland. These
investigators also observed that the combination of high exog-
enous E2 and high dietary isoflavones reduced circulating (47)
and intra-breast (48) E2 concentrations in monkeys. Further-
the endometrium was noted (48). However, when the exposure
development of the testis were affected (49). These findings
suggest that although adult exposure to genistein does not elicit
of nonhuman primates, early-life exposure may have adverse
Human data. In humans, the estrogenic effects of isoflavones
alone or in soy foods have been investigated in numerous studies
with conflicting outcomes. Although the data by Lu et al. (50)
suggested that soy intake reduces circulating estrogen levels,
(51,52). The effects of soy intake or exposure to isoflavones on
mammary epithelial cell proliferation have also been studied.
Some of these studies indicate that soy protein isolate increases
the volume of breast fluid (marker of increased breast cancer
risk), presence of hyperplastic epithelial cells, and cell prolifer-
ation (53,54). One study found that soy increased expression of
pS2, suggesting an estrogenic effect on the breast (55). Studies
thathaveexploredtheeffect ofconsumptionofisoflavones alone
or in soy foods on high mammographic density, a strong marker
None of these studies, even those from the same authors, used
similar amounts of isoflavones or foods. In the study by
Maskarinec et al. (57), the nutritional intervention consisted of
a choice of 2 daily servings of soy. This serving was defined as the
amount of food that contained ;25 mg of isoflavones and
31 g soy protein powder, or 23 g roasted soy nuts. In contrast,
another study by Maskarinec et al. (58) used purified forms of
isoflavones, where soy germ was the main source. This is a sig-
providing a unique isoflavone profile that no other traditional or
Westernized soy food has. Thus, these studies used food sources
that greatly differ in the amount and profile of isoflavones and
other bioactive component factors that dictate final bioaccesi-
bility and bioavailability of isoflavones.
In summary, human studies that have investigated changes in
circulating hormone levels or mammographic density in pre- or
postmenopausal women bydiets high in isoflavones from dietary
supplements or soy foods have found no significant effects, sug-
gesting that they do not alter breast cancer risk. However, these
studies have used moderate doses of isoflavones, reflective of
Asian soy food consumption, and it is possible that higher doses
could yield different results.
Epidemiological studies on soy intake and
breast cancer risk
Two meta-analyses have been performed that investigated the
by Trock et al. (60) and included 18 studies. The findings of this
study indicated that soy intake was associated with reduced
in risk was strongest among premenopausal women. However,
significantly reduce the risk of developing breast cancer [odds
2 y later by Wu et al. (61) concluded the opposite, i.e. that no
protective effect was seen in Western women who consumed
either no or low levels of soy products, most of which are not
traditional soy foods, but a significant reduction was seen in
Asian women and Asian American women [OR = 0.71; 95% CI
0.60–0.85]. The differing conclusions reached by these 2 meta-
analyses are most likely caused by inclusion of Asian American
women in the Western category by Trock et al. (60) and in the
Asian category by Wu et al. (61).
Together, these findings suggest that a protective effect is seen
among Asian American women who continue consuming mod-
women who adopt Western dietary habits. Thus, these women
are able to maintain the low breast cancer risk of Asian countries
if they continue consuming soy, but if their diet becomes
Westernized, these women exhibit the same high risk as Cauca-
closely related to some other dietary habit or lifestyle that
provides protection against breast cancer. For example, Asian
consume more rice, fish, vegetables, and tea and less fat than
Caucasians. The reason why a protective effect is not seen in
equivalent amounts of genistein aglycone (750 mg/g) on estrogen-
dependent MCF-7 tumor growth in athymic mice. Cells were injected
subcutaneously into dorsal flanks of ovariectomized athymic mice.
After tumor establishment, E2 pellets were removed and mice were
randomly assigned to treatment groups. Positive control (PC) mice
were reimplanted with a new E2 pellet. Both the negative control (NC)
and PC mice were fed a low-phytoestrogen control diet (AIN-93G).
Treatment groups also included an AIN-93G diet with genistein (GI),
mixed isoflavones (MI), Novasoy (NS), molasses (MOL), and soy flour
+ mixed isoflavones (SF + MI). Tumors were monitored weekly and
tumor size was calculated and is expressed as mean cross sectional
area (mm2) of all tumors in each treatment group 6 SEM. Data from
wk 11 of treatment is presented. Figure reproduced with permission
Food matrix modulates the estrogenic effects of
soy and even the lowest level of intake, which corresponds to high
intake in Western countries, is enough soy to reduce the risk.
Additionally, the reduction in risk may be seen only if soy is
consumed throughout life or during periods before or during
extensive development of the breast, i.e. puberty and pregnancy.
Most studies conducted using adult animals do not support
an association between an exposure to genistein and mammary
tumorigenesis (62,63). These studies exposed animals to ge-
nistein by injection or feeding them genistein, isoflavones, or soy
isolate. However, animal studies show that soy/genistein intake
before puberty onset provides strong protection (64).
Soy intake during childhood and adolescence and later
breast cancer risk. Five case-control studies have investigated
whether soy intake during childhood or adolescence affects later
breast cancer risk. A study by Korde et al. (65) assessed (sep-
arately during childhood, adolescence, and adulthood) soy in-
take in 966 controls and 597 cases who were 20–55 y old at the
time of the interview, and found a significantly reduced risk
among those women who consumed the highest level of soy
either during childhood (5–11 y) or adult life (over 20 y) (Table
1) [OR = 0.42 (95% CI:0.20–0.90); P , 0.02].Three other case-
control studies found a significantly reduced risk among those
who consumed the highest quartile of soy between ages 12 and
19 y compared with those consuming the lowest quartile (Table
1). In 2 of these studies, both conducted in Asian women living
either in Asia (66) or the US (67), the risk was one-half of that in
the comparison group (lowest soy intake quartile). Soy intake in
these studies is reflective of what is commonly consumed in Asia
or the US among Asians, i.e. 1–2 servings/d of traditional Asian
soy products. Western soy products prepared using isoflavone
supplements can contain several-fold higher levels of, e.g., ge-
nistein and therefore may have estrogenic effects. The only study
involving Caucasian women showed the lowest, but still sig-
nificant, reduction in risk (68). One study conducted in Asian
women did not find any protective effect by adolescent soy in-
take and breast cancer risk (69). However, this study showed
that women who consumed soy both during early life and
adulthood had a significantly reduced risk of breast cancer
Why childhood soy consumption reduces later breast
Because genistein acts through activation of ERa and ERb, it is
not surprising that prepubertal genistein exposure causes a long-
lasting change in the expression of the ER. In rats and mice,
pubertal exposure to genistein causes a persistent upregulation
of both ERa and ERb, whereas E2 downregulates ERa and
upregulates ERb in the mammary gland (70,71). Similar findings
have been reported in humans; women consuming soy early in
life had elevated estrogen and progesterone receptor expression
in benign mammary tissue (72).
High expression of ERa in normal mammary tissue does not
necessarily mean increased breast cancer risk. This is because
proliferating mammary cells do not express ERa (73); only
proliferating mammary tumor cells do (74). The increase in E2-
induced proliferation requires that ER activates amphiregulin,
which then binds to epidermal growth factor receptor (EGFR);
activation of EGFR by amphiregulin leads to mammary epithe-
lial proliferation (75). Amphiregulin is a tyrosine kinase, as are
EGF, transforming growth factors, and others, which in addition
to EGFR bind to other members of tyrosine kinase receptor
family, such as human epidermal growth factor receptor 2
(Her2). Genistein is a potent tyrosine kinase inhibitor (76) and
therefore may prevent E2-induced cell proliferation. This is
supported by findings in numerous studies showing that expo-
sure to genistein during the prepubertal period inhibits mam-
mary epithelial cell proliferation (77,78). We have recently
found that prepubertal dietary exposure to genistein, at the level
Asians consume it, silences the expression of amphiregulin in the
mouse mammary gland (S. de Assis, A. Warri, L. Hilakivi-
Clarke, unpublished data). In addition, we (S. de Assis, A. Warri,
L. Hilakivi-Clarke, unpublished data) and others (72) have
shown in mice and humans that prepubertal genistein exposure
(mice) and soy intake (humans) reduces Her2 expression in
mammary tumors. Genistein also has been reported to down-
regulate Her2 in human breast cancer cells (79). Together, these
findings suggest that although genistein/soy upregulates ERa, it
inhibits mammary cell proliferation, possibly by silencing
amphiregulin and preventing EGFR activation.
Inaddition to changesinER,genistein affects the expression of
many transcription factors that are directly or indirectly regulated
by ER, including tumor suppressor genes BRCA1 (70,80) and
PTEN (81), both in vitro and vivo at physiological concentrations
of this isoflavone. Our unpublished data indicate that pubertal
genistein exposure causes a persistent upregulation of caveolin-1,
also a tumor suppressor regulated by estrogens (82). These tumor
suppressor genes have multiple functions, including inhibiting the
PI3K/Akt signaling pathway, repairing DNA damage, and induc-
ing epithelial differentiation (83–87). PTEN (88) and caveolin-
1 (89) both regulate Wnt/b-catenin signaling, which in turn has
been linked to several cancers, including breast cancer (90). Fur-
ther, hyperactive Wnt/b-catenin signaling leads to dysregulation
of mammary stem cell behavior (91), which may be the corner-
stone of cancer susceptibility and growth.
Several microarray analyses have studied genes modified by
genistein, most of which were done using human breast cancer
OR and 95% CI of breast cancer risk in women consuming different levels of soy during
childhood/adolescence and adult life1
Shu et al. 2001 (66)
Wu et al. 2002 (67)
Thanos et al. 2006 (68)2
Korde et al. 2009 (65)
Lee et al. 2009 (69)
0.42 (0.20–0.90) 0.71 (0.53–0.95)
1Breast cancer risk was lowest in women who consumed high levels of soy both early in life and adulthood.
2Isoflavone intake was measured in this study.
Soy and breast cancer2329S
cells, such as MCF-7 cells. Lavigne et al. (92) found that phy-
siological doses of genistein (1–5 mmol/L) elicited an expression
pattern indicative of increased mitogenic activity, while a phar-
macological dose (25 mmol/L) generated a pattern related to a
high level of apoptosis and decreased cell proliferation in these
cells. These findings are consistent with the high breast cancer
cell proliferation seen with physiological genistein doses and
inhibition of growth at pharmacological doses (1).
Su et al. (93) isolated mammary epithelial cells from the
glands of rats fed a diet containing no isoflavones, soy protein
isolate, or genistein throughout the fetal period until killing on
postnatal d 50 and performed gene microarrays. They found
that genistein affected Wnt and Notch signaling, indicating an
effect on stem cell behavior, i.e. proliferation and differentiation.
In a subsequent study, Su et al. (94) investigated the effects of
lifetime genistein exposure on adhesion molecule E-cadherin.
Results from this study indicated that E-cadherin was upregu-
lated in the adult mammarygland bygenistein; this might leadto
inhibition of tumor progression.
Although genistein has been reported to upregulate several
tumor suppressor genes and downregulate oncogenes, it is not
known whether there is a causal relationship between these
transcriptional changes and reduced tumorigenesis. Our recent
data generated in heterozygous Brca1+/2 knockout mice
indicate that upregulation of this tumor suppressor is required
for the mammary cancer-reducing effects of prepubertal dietary
genistein exposure (S. de Assis, A. Warri, L. Hilakivi-Clarke,
Genistein modulates gene expression by
The mechanisms responsible for persistent changes in gene
expression in the mammary glands of individuals exposed to
genistein or other (estrogenic) compounds before onset of
puberty may involve epigenetic modifications. Epigenetic regu-
lation of gene expression has been identified as the key process
allowing the environment during embryonic development to
interact with the genotype, resulting in the observed phenotype
(95,96). These epigenetic mechanisms may control gene expres-
sion, which influences the differentiation process of the mam-
mary epithelium. For example, DNA hypomethylation induced
by treatment with 5-aza-29 deoxycytidine prevents epithelial
differentiation, indicating that DNA methylation is essential for
this process (97).
We and others have shown that prepubertal genistein expo-
sure increases the differentiation of the mammary epithelial tree
(64). Because differentiation of mammary epithelial structures is
closely related to breast cancer risk (98), it is possible that the
mammary gland morphology is epigenetically induced. For
example, Wnt/b-catenin signaling regulates progenitor cells;
overactivity of this pathway leads to excessive mammary
outgrowth (90,91). Chromatin remodeling factor Pygo2 epige-
netically regulates transcriptional activation of b-catenin down-
stream of Wnt signaling (99). As discussed above, Wnt/b-catenin
is one of the pathways affected by genistein/soy (93,94) and,
risk by altering gene expression epigenetically in a manner that
affects mammary epithelial cell proliferation and differentiation.
Interestingly, genistein seems to induce both gene promoter
methylation (100) and demethylation (101). When genistein is
administered in utero, an increase in methylation takes place
(100). Specifically, maternal exposure to genistein increases
methylation of 6 cytosine-guanine sites in a retrotransposon
upstream of the transcription start site of the Agouti gene at the
offspring that exhibit the pseudo agouti phenotype linked to
the DNA hypomethylating effect of an endocrine disruptor,
bisphenol A (102). However, genistein also can reactivate genes
by promoter demethylation and active histone modification
(103). It is not known whether prepubertal genistein exposure
might increase or reduce methylation patterns.
Safety of soy intake after breast cancer diagnosis
Because of the apparent estrogenicity of genistein is soy, women
diagnosed with breast cancer have been advised to avoid it. The
concern about soy’s ability to promote breast cancer growth is
heightened by our findings (40,104) obtained in MCF-7 human
breast cancer cells in vitro andin vivo. We have shown that doses
of genistein mimicking human exposure levels increase prolif-
eration of these cancer cells similarly to E2. Even more
concerning is that genistein prevents the action of tamoxifen
to inhibit the growth of the MCF-7 breast cancer cells in vitro
and in vivo (105).
In 2009, 2 human studies were published that investigated
the recurrence and metastasis of breast cancer in relation to soy
intake or circulating isoflavone levels after diagnosis. A study
done in 1954 female breast cancer survivors in the US
determined their genistein, daidzein, and glycitein intake using
the Fred Hutchinson Cancer Research Center FFQ and asking
survivors about their use of herbal supplements and herbs (106).
The mean follow-up time for these women was 6.31 y. No
evidence of an association between risk of recurrence and intake
of genistein [HR = 0.95 (95% CI 0.52–1.75)] or daidzein [HR =
0.96 (95% CI 0.52–1.76)] was found, but high glycitein intake
OR and 95% CI of breast cancer risk in women consuming different levels of soy during childhood/adolescence and adult
AuthorsCases vs. controlsAdult intake
ethnicity LowMedium High
Wu et al. 2002 (67) 501 cases vs. 594 controlsLow
1 0.77 (0.51–1.16)
Korde et al. 2009 (65) 597 cases vs. 966 controls0.44 (0.18–1.03)
Lee et al. 2009 (69) 592 cases vs. 72,223 totalAsian
1Breast cancer risk was lowest in women who consumed high levels of soy both early in life and adulthood.
was nonsignificantly associated with reduced risk (P-trend ,
0.10) (Fig. 3). The study also addressed whether soy intake
affected the risk of recurrence among women using tamoxifen,
because animal studies have indicated that genistein prevents
tamoxifen action in MCF-7 human breast cancer cells in vitro or
in vivo (106). Tamoxifen users who consumed the highest level
of soy products exhibited no increase in the risk of recurrence,
but nonusers did. Women who had never taken tamoxifen but
were estimated to have the highest intake of daidzein [HR = 2.40
(95% CI 0.93–6.18)] or genistein [HR = 2.42 (95% CI 0.95–
6.21)] exhibited an almost significant increase in risk of
recurrence. Because tamoxifen is not commonly given to women
who exhibit ER-negative breast cancer, which is more aggressive
than ER-positive tumors, the results are not surprising.
The study by Shu et al. (107) included 5042 Chinese breast
cancer survivors diagnosed between 2002 and 2006 and
followed for 3.9 y on average. Most of these women had radical
mastectomy. Soy protein and isoflavone intakes were assessed
from FFQ and by interview. The data indicated that women who
continued to consume soy after diagnoses and treatment had
significantly lower risk of recurrence than women in the lowest
soy intake category [soy protein HR = 0.68 (95% CI 0.54–0.87);
soy isoflavone HR = 0.77 (95% CI 0.60–0.98)]. The protective
effect occurred in both women diagnosed with ER+ or ER2
breast tumors and in tamoxifen users and nonusers. Although
soy intake may not have affected their risk of developing breast
cancer (60), these results provide powerful evidence in support
of soy reducing the risk of recurrence among women who have
consumed soy throughout their life.
It is puzzling why the data obtained using well-established
breast cancer models that are used widely among investigators
and findings in the 2 recent human studies are in stark contrast
with each other.One likelyexplanation for thesurvival benefit in
Chinese women consuming high levels of soy is that they
probably consumed soy throughout the life. Although they
developed breast cancer despite soy intake, the tumors may
differ among the high and low soy consumers. Further, soy
intake might inhibit the action of factors that are associated with
breast cancer recurrence, such as angiogenesis or genes that
promote the spread of cancer (108). Maskarinec et al. (72) found
that breast tumors in women who consumed soy early in life
expressed lower levels of HER2/neu protein and had reduced
PCNA staining compared with tumors in women consuming
low levels of soy. We have obtained similar data in mice fed a
genistein-containing diet before puberty (S. de Assis, A. Warri, L.
Hilakivi-Clarke, unpublished data).
Another factor that might play a role in explaining the
differences inthe results obtained invitroand invivo studies that
used MCF-7 human breast cancer cells and recent human studies
is that studies in MCF-7 cells do not take into account epithelial-
stromal interactions, which are increasingly recognized as being
critical for breast cancer initiation and growth (109,110). As
discussed above, activation of the ERa leads to cell proliferation
through stromal EGFR (75). Further, normal stroma has been
shown to prevent progression of transformed epithelial cells,
whereas if the stroma is altered, it supports malignant growth
and spread of (epithelial) breast cancer (111).
In conclusion, the breast cancer studies discussed in this
review mostly have been doneusing genistein. Only afew studies
have used whole soy and therefore it is not clear whether the
effects of, e.g., genistein alone, genistein in isoflavone mix,
genistein in soy protein isolate, or genistein in soy beans have
similar biological effects. It is important to consider the potential
interactions between phytoestrogens and other bioactive com-
ponents in the food matrix that could either enhance or reduce
their ultimate effect on health. Westernized soy products are
quite different from those consumed in the traditional Asian
diet. Most Asian soy products use whole soybeans with or
without fermentation. Soy products or second generation soy
foodsin the US are mostly based on soy protein at different levels
of purification or extraction such as texturized vegetable protein
(;45% protein), soy protein concentrate (;70% protein), or
isolates (;90% protein), each with a different profile of nutrient
and non-nutrient compounds, including isoflavones and sapo-
nins(112,113). It is likely thatprocessing of soy foodsmodulates
the profile of isoflavones and modifies their bioaccesibility and
5042 Chinese breast cancer survivors (102) (B). Relative risk (RR) and 95% CI are shown for glycitein, genistein, and daidzein intake in A and for
isoflavone and soy protein intake in B. The study done in Western women showed no protective effect and an almost significantly increased risk
of recurrence among those not taking tamoxifen and having the highest intake of genistein and daidzein. In contrast, the study done in Chinese
women found a significantly reduced risk of recurrence in women having the highest level of isoflavones and soy protein in their diet. Reproduced
Risk of recurrence of breast cancer by soy intake, assessed using FFQ, among 1954 Western breast cancer survivors (101) (A) and
Soy and breast cancer2331S
bioavailability, but how these differences affect breast cancer
risk and risk of recurrence need to be investigated.
soy isoflavones remainsinthespotlight asapossible “treatment”
to reduce menopausal symptoms and prevent bone loss. The
beneficial effects of soy are more convincing if soy has been
consumed throughout life rather than if the intake starts at
menopause (114,115). In the breast, soy intakeduring childhood
and adolescence might provide lifelong protection against breast
intake (65,67). Although 2 recent human studies in breast cancer
survivors didnotindicate adverseeffects (106,107)andsuggesta
regularly, more studies are needed to determine whether Western
soy products or isoflavone supplements are safe for women
diagnosed with breast cancer.
L.H-C., J.E.A., and W.H. wrote the paper and L.H-C. had
primary responsibility for the final content. All authors read and
approved the final manuscript.
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