P H Y T OE S T R O GE N S
A ND T H E RI S K O F B RE AS T
A R E V I E W OF T HE L I T E RAT UR E
C A NCE R
Authors: P. D. Gikas, K. Mokbel.
St George’s Hospital, London, United Kingdom.
Corresponding Author:
Professor Kefah Mokbel. MS, FRCS
Professor at Brunel Institute of Cancer Genetics
Consultant Breast & Endocrine Surgeon.
The Princess Grace Hospital
42-52 Nottingham Place
London W1M 3FD
Tel: (0044) 207 908 2040
Fax: (0044) 207 908 2275
e-mail: kefahmokbel@hotmail.com
website: www.breastspecialist.co.uk
1
A B S T RA C T
B AC K GR O U N D : Interest in the physiological role of bioactive compounds present in
plants has increased dramatically over the last decade. Of particular interest in relation
to human health are the class of compounds known as the phytoestrogens, which
embody several groups of non-steroidal estrogens including isoflavones and lignans
that are widely distributed within the plant kingdom. Epidemiological studies suggest
that diets rich in phytoestrogens, particularly soy and unrefined grain products, may
be associated with low risk of breast cancer. This review presents the studies
published so far exploring a link between dietary phytoestrogens and breast cancer
risk.
M E T H OD S : A Medline search was conducted using the keywords breast cancer, soy,
phytoestrogens and lignans. Further articles were obtained by cross-matching
references of relevant articles. Twenty one case-control and 15 prospective studies
were identified since 1978. One meta-analysis and several review articles were also
noted.
R E S UL T S : Results from previous studies were analysed and comparisons were made
between each type of study. Controversy exists regarding this subject and we found
conflicting evidence in recent literature regarding this hypothesis.
C O NC L U S I ON : There is no clear evidence that phyto-estrogens intake influences the
risk of developing breast cancer.
Keywords: breast cancer, phytoestrogens, soy, isoflavones, lignans
I NT R O D U C T I O N
2
Phytoestrogens are natural plant substances. The three main classes are
isoflavones, coumestans and lignans [1, 2]. Isoflavones are the most frequently
studied and are present in large amounts in soybeans and soy products (e.g. miso,
tofu). Their scientific interest lies in the fact that they exhibit structural similarity to
mammalian estrogens. The most important isoflavones are genistein and daidzein.
Coumestans occur in bean sprouts and fodder crops; they have received little
scientific interest so far. Lignans are not present in our diets as such, but as
precursors, plant lignans, which are then modified by gut microflora to mammalian
lignans. Plant lignans are present in fibre-rich food such as flaxseed, unrefined grain
products (e.g. rye) and some berries [3, 4].
Plant compounds do have biological activity. Soybeans were shown to cause an
infertility syndrome in cheetahs in Cincinnati Zoo, which was reversible upon
removing soy from their feeds [5]. Based on this and other observations in the past a
potential preventive or causal effect of phytoestrogens on the occurrence of human
disease in general and cancer in particular has been suggested.
Breast cancer is one of the most common cancers in the western world. It
claimed 40,200 lives in the United States and 13,700 lives in the United Kingdom
respectively in 2003. Considerable variations in incidence and mortality rates exist
between different geographic regions. Recent epidemiological studies cited multiple
risk factors relating to breast cancer including age, family history, body weight,
number of pregnancies, hormone concentration and metabolism, exposure to
radiation, and breast-feeding. One of the possible explanations for these geographic
differences is the variation in environmental exposures including diet [6, 7, 8].
This review presents the studies published so far exploring a link between
dietary phytoestrogens and breast cancer risk.
A NT I - C A R C I N O GE N I C P OT E NT I AL O F P HY T O E S T R OG E NS O N B RE A S T
C A NCE R R I S K
ISOFLAVONES
The postulated anti-carcinogenic mechanism of isoflavones involves their weak
estrogen like activity [9]. By binding to estrogen receptors they initiate a modest
response and at the same time prevent binding of more potent estrogens. Furthermore,
numerous recent studies in humans have demonstrated effects of isoflavones on
hormone levels, such as a reduction in serum estradiol and a decrease in plasma FSH
and LH [61-63]. These data suggest that phytoestrogens might also exert an anticarcinogenic effect by altering estrogen metabolism.
Several in vitro studies show that isoflavones inhibit the growth of a wide range
of both hormone-dependent and hormone independent cancer cells. Phytoestrogens
have also been shown in the lab to act as antioxidants, inhibit angiogenesis and
stimulate apoptosis in breast cancer cells, therefore potentially limiting tumour spread
[10, 11]. Valachovicova et al. investigated the effect of soy isoflavones on the
behaviour of highly invasive breast cancer cells and found that these substances can
inhibit adhesion and motility of malignant human mammary cells by a variety of
signalling pathways [12]. Dave et al. recently demonstrated that the soy isoflavone
genistein promotes apoptosis in mammary epithelial cells by inducing the tumour
suppressor gene PTEN [13].
Animal studies so far have shown promising results in terms of the anticarcinogenic potential of phytoestrogens. Soybeans in particular, when used to
supplement rat diets exert a negative effect on tumour size and number [14]. A recent
study from Canada indicates that dietary intervention (in the form of a soy enriched
3
diet) following cancer surgery can reduce the outgrowth of seeded human mammary
tumour cells in mice [15]. Luijten et al. however, failed to show any significant
protective effect of soy-derived isoflavones on spontaneous mammary tumour
development in a mouse animal model [16]. These non-uniform results simply
underline the need for the development of well-characterised, clinically relevant
animal models to further elucidate the effects on phytoestrogens on carcinogenesis.
Studies that have looked into geographical differences in breast cancer
occurrence are consistent with a protective effect of isoflavones. Women in eastern
populations, that have diets rich in soy products (used in general as a proxy for the
intake of isoflavones), show lower breast cancer incidence [17].
Ten epidemiological case-control studies have so far looked into the relation
between dietary soy intake and the risk for breast cancer [18-27] (Table 1). Of them
the majority do not find a protective effect for frequent soy intake [18, 21-23, 26].
Three have shown clear protective effects, when soy products are consumed
frequently, only in pre-menopausal women [19, 20, 27]. One recent study
demonstrated protective effects of soy food intake at adolescence and at older ages
but only when consumed in high amounts [24]. The main disadvantage with all these
studies is the use of dietary questionnaires to quantify soy intake i.e. they are not
based on accurate objective measurement of soy food content. Moreover, recall bias,
as with any case-control study, is a problem potentially limiting the validity of the
results obtained [1].
Eight prospective studies so far explore the link between isoflavones and breast
cancer [28-35] (Table 2). Four demonstrate small decreases in breast cancer
occurrence when high amounts of soy (as a proxy for isoflavones) are ingested but
none of the results are statistically significant [28-31]. One study assessed the effect
of dietary soy food supplementation on estrogen levels in post-menopausal women
but failed to demonstrate any significant reduction in hormonal levels [35]. A further
study examined the effect of soy foods on menstrual cycle length and circulating sex
hormone levels in pre-menopausal women; no significant intervention effect was
demonstrated [32]. Maskarinec et al. explored the effect of soy foods and lifetime soy
intake on mammographic densities; after two years no significant differences where
observed between the control and intervention groups [33]. Sartippour et al. carried
out a very interesting pilot clinical trial (involving only 17 cases) in order to elucidate
any interaction between short-term isoflavone (i.e. soy) supplement administration
and breast cancer growth. The study was based on human breast cancer tissue and
blood obtained prior to and after isoflavone supplement treatment in the same patient.
The apoptosis/mitosis ratios in isoflavone-treated cancer specimens were not
significantly different from those of control untreated cancer specimens [34].
One recent, double-blind, randomised trial explored whether oral soy
supplements can prove useful in the treatment of menopausal symptoms in women
treated for breast cancer. There was no statistical difference in menopausal symptom
scores or quality of life between the two arms of the study [36].
4 case-control studies have measured urinary excretion of isoflavones in relation
to breast cancer [37-40] (Table 3). All four are suggestive of protective effects, in
terms of breast cancer risk, of higher excretion levels of isoflavones, however only
one study obtained a statistically significant result [37]. However, it is not
unreasonable to question the relevance of phytoestrogen levels in urine samples
collected following diagnosis of breast cancer to induction or progression of the
disease many years earlier i.e. causal interpretation of these observations is
significantly limited.
4
Two prospective studies have looked into the relevance of urinary isoflavone
excretion and breast cancer [41, 42] (Table 3). One has demonstrated a small nonstatistically significant breast cancer risk reduction [41]. Interestingly in the other
study, all isoflavones measured were associated with an increased risk of breast
cancer, findings which were statistically significant only for equol (a daidzein
metabolite) [42].
LIGNANS
Precursors of mammalian lignans are found in fibre-rich food, such as flaxseed,
unrefined grain products, particularly rye, and some berries. They are metabolised in
the mammalian gut to produce the phytoestrogens enterolactone and enterodiol.
In vitro and animal studies so far have produced mixed results. Chen et al.
concluded that lignans and tamoxifen, alone or in combination could reduce human
breast cancer cell adhesion, invasion and migration in vitro [52]. Wang et al
demonstrated that dietary flaxseed can reduce the growth and metastasis of human
estrogen receptor negative breast cancer in mice [53]. Magee et al however did not
show any significant effect of lignans on invasion of a breast cancer cell line in vitro
[54].
A number of epidemiological studies have also researched the association
between lignans and breast cancer risk. Smith-Warner et al. in a pooled analysis of
eight prospective studies found a borderline significant reduced breast cancer risk for
the highest lignan intake [55].
Seven case control studies so far have looked into a possible association
between dietary lignan intake and breast cancer risk [37, 43-48] (Table 4). The
findings of Kilkkinen et al., in a Finish study, failed to support the hypothesis that
high serum lignan concentration is associated with a reduced breast cancer risk [48].
Six studies demonstrated a reduced breast cancer risk which was however limited to
pre-menopausal women and estrogen receptor negative tumours [37, 43-47]. The
main limiting characteristic of these is that lignan levels were measured after disease
development hence seriously limiting causal interpretation.
Boccardo et al. assessed retrospectively, the relationship between serum lignan
concentrations and the occurrence of breast cancer in women with palpable cysts.
Although a small study it did confirm a protective effect of lignans on breast cancer
risk [50].
Thompson et al. in a randomised double-blind placebo-controlled clinical trial
investigated the effects of dietary flaxseed on tumour biological markers and urinary
lignan excretion in postmenopausal patients with newly diagnosed breast cancer.
Reductions in c-erbB2 expression and an increase in apoptosis were observed in the
intervention group suggesting that dietary flaxseed has the potential to reduce tumour
growth in breast cancer patients [51].
Two prospective studies have failed to demonstrate any protective role of
lignans in the development of breast cancer [40, 49] (Table 4).
C A RCI N O GE N I C P O T E N T I A L O F P H YT OE S T R OG E N S ON B R E AS T C AN CE R
RISK
Overall the impression is form the paragraphs above that phytoestrogens may
exert anti-carcinogenic potential by altering blood levels of relevant hormones and/or
exhibiting antioxidant, anti-angiogenic or pro-apoptotic effects.
However, phytoestrogens have also significant estrogenic properties in both in
vitro and in vivo models [56, 57]. It is a well known fact from epidemiological and
clinical data that lifetime exposure to estrogens has significant influence on increased
5
breast cancer risk [58-60]. It is thus not easily conceivable how phytoestrogens could
prevent the development or growth of breast cancer.
D I S CUS S I ON
Interest in the physiological role of bioactive compounds present in plants has
increased dramatically over the last decade. Of particular interest in relation to human
health are the class of compounds known as phytoestrogens, which embody several
groups of non-steroidal estrogens including isoflavones and lignans that are widely
distributed within the plant kingdom. These compounds have a wide range of
hormonal and non-hormonal activities in animal and in vitro models, and these
suggest plausible mechanisms for potential physiological effects of diets rich in these
compounds in humans. Experimental and epidemiological data are available to
support the concept that phytoestrogen-rich diets exert physiological effects and
preliminary human studies suggest a potential role for dietary phytoestrogens in
hormone-dependent disease [64].
The biological action of these compounds is complex and their ultimate cellular
actions are determined by many factors including the phytoestrogen compound
studied, cell line used species (including genetic polymorphisms) and tissue under
examination. The principal postulated anti-carcinogenic mechanism involves their
weak estrogen like activity. Phytoestrogens bind to estrogen receptors, initiate only a
modest response and at the same time they block the binding of more potent
estrogens. There is structural similarity to the potent synthetic anti-estrogen tamoxifen
[1, 9]. Furthermore numerous other biological activities independent of the ER have
been ascribed to phytoestrogens such as antioxidant, anti-proliferative, antiangiogenic and pro-apoptotic effects [10, 11]. Recent studies suggest that human gut
bacterial metabolism of dietary phytoestrogens can alter their biological activities. As
such, inter-individual differences in the ability to harbour certain intestinal bacteria
might be associated with inter-individual differences in metabolism of phytoestrogens
and hence variations in health and/or disease susceptibility (Atkinson et al. has shown
that only 30%-50% of the human population can metabolise daidzein to equol) [65].
The anti-carcinogenic potential of isoflavones on breast cancer risk was
evaluated in 19 studies that measured dietary soy (product) (or isoflavones) intake in
relation to breast cancer [18-36]. Nine of these studies were prospective and none of
these prospective studies found any statistically significant protective effect [28-36].
From the remaining 10 case-control studies we conclude that if indeed any protective
anti-carcinogenic effect is present it seems to apply to women that consume high
amounts of soy at younger ages [18-27]. We need however to underline the fact that
the majority of these studies were done in Asian populations were the consumption of
soy is homogeneously high. Relations with breast cancer may thus be difficult to
detect if consumption for the total population is above a threshold level. Moreover
one should keep in mind that the studies included overall healthy subjects. It is not
clear what the effect of increased consumption will be in women at high risk of breast
cancer (i.e. previous cancer, genetic predisposition) [1]. There were six studies that
measured urinary excretion of isoflavones in relation to breast cancer risk [37-42].
Only two of them were prospective, one reporting a non-significant reduction in
breast cancer risk [41], the other a significantly increased breast cancer risk for urine
and serum levels of equol (an isoflavone metabolite) [42]. In the latter study however
dietary intake of isoflavones was low among cases and hence the resulting equol
concentrations were also low.
6
The anti-carcinogenic potential of lignans on breast cancer risk was evaluated in
11 studies [37, 40, 43-51]. Of them only four were prospective; two failing to
demonstrate any protective effect [40, 49]; one did show a reduced breast cancer risk
with increased serum enterolactone concentration [50], and finally the fourth study
revealed a reduced breast tumour marker expression with increased urinary lignan
excretion [51].
We can easily see from the data above that almost all studies so far (29 out of 30
epidemiological studies) showed no evidence for an increased risk of breast cancer
with increased phytoestrogen intake. An absence of risk is important since the
putative physiological effects of phytoestrogens have created a market that has been
utilised by the nutritional industry. We should not forget that soya has been consumed
for thousand of years in Asian countries and over many generations of exposure there
is significant evidence for safe use [1].
Nevertheless, in order to understand how phytoestrogens may act, we need more
information on the cell- or tissue- or organ-specific actions of the individual
compounds. Long-term animal studies with well characterised and standardised
phytoestrogen preparations are needed to investigate the potential beneficial and
adverse effects. Systemic pharmacokinetic and dose-response studies are required to
determine which dietary compounds can be absorbed in efficiently enough, and to
estimate the amounts in diet sufficient to exert the biological effects. Finally after the
possible adverse effects have been ruled out, long term clinical trials with well
characterised and standardised phytoestrogen preparations are necessary to confirm
the beneficial health effects in humans and most importantly the putative anticarcinogenic potential of these compounds.
7
TABLE 1. OVERVIEW OF EPIDEMIOLOGICAL STUDIES
CANCER RISK - CASE CONTROL STUDIES
Study Population
Design
Cases
ON
DIETARY SOY
AND
Findings
BREAST
Reference
Controls
Japanese (1985)
Singapore (1991)
212
200
212
420
Japanese (1995)
1186
21,295
Chinese (1995)
Chinese, Japanese,
Filipino population in
USA (1996)
834
597
834
966
USA and Canada
(1997)
Chinese in Shanghai
(2001)
Chinese in Shanghai
(2001)
140
222
1459
1556
1459
1556
Non-Asian multiethnic
US-women
German
1326
1657
278
666
No protective effect
Protective effect for frequent soy
consumption in pre-menopausal women
Protective effect for frequent soy
consumption in pre-menopausal women
No protective effect
Protective effects significant only for nonUS born Asian Americans (authors
hypothesised that soy intake is protective
only when consumed at higher doses and
at younger ages)
No protective effect
[18]
[19]
Protective effect of soy intake at
adolescence
Protective effect of soy intake at older
ages but only if consumed in high
amounts
No protective effect
[24]
Protective effect for frequent soy
consumption in pre-menopausal women
[27]
[20]
[21]
[22]
[23]
[25]
Same study
as above
[26]
8
TABLE 2. OVERVIEW OF EPIDEMIOLOGICAL STUDIES
CANCER RISK - PROSPECTIVE STUDIES
Study Population
Japanese (1978)
Japanese (1990)
USA (1996)
Japanese (1999)
USA (2004)
USA (2004)
USA (2004)
USA (2005)
UK (2005)
Design
6860 males with 86 married
to a woman with breast
cancer
142,857 women, 241 deaths
Iowa Women’s Health
Study, 1018 cases
34,759 women, 427 cases
Dietary interventional study
on 220 healthy premenopausal women
Dietary interventional study
on 220 healthy premenopausal women
Observations made on
breast cancer tissue obtained
before and after isoflavone
supplementation in the same
patients
Dietary interventional study
on 57 healthy postmenopausal women
Dietary interventional study
on 72 breast cancer patients
ON
DIETARY SOY
AND
BREAST
Findings
No statistically significant
decrease in breast cancer risk
Reference
[28]
No statistically significant
decrease in breast cancer risk
No statistically significant
decrease in breast cancer risk
No statistically significant
decrease in breast cancer risk
No significant intervention effect
on any of the serum sex
hormones
No significant intervention effect
on mammographic densities
[29]
No statistically significant
decrease in the apoptosis/mitosis
ratio in tissues from the
isoflavone intervention group.
[34]
No significant intervention effect
on any of the serum sex
hormones
No significant intervention effect
in menopausal symptom scores
or quality of life
[35]
[30]
[31]
[32]
[33]
[36]
9
TABLE 3. OVERVIEW OF EPIDEMIOLOGICAL STUDIES
EXCRETION AND BREAST CANCER RISK
Study Population
Australian (1997)
Design
144 cases, 144 controls
Case Control Study
Chinese (1999)
60 cases, 60 controls
Case Control Study
18 cases, 20 controls
Case Control Study
250 cases, 250 controls
Case Control Study
88 cases, 268 controls
Prospective study
114 cases, 219 controls
Prospective study
Australian (2000)
Chinese (2002)
Netherlands (2001)
UK (2004)
ON
URINARY ISOFLAVONES
Findings
Statistically significant
protective effect only for urinary
excretion of equol (a metabolite
of daidzein)
No statistically significant
protective effect
No statistically significant
protective effect
No statistically significant
protective effect
No statistically significant
protective effect
Urine and serum equol
associated with significant
increase in breast cancer risk
Reference
[37]
[38]
[39]
[40]
[41]
[42]
10
TABLE 4. OVERVIEW OF EPIDEMIOLOGICAL STUDIES ON LIGNANS AND BREAST CANCER
RISK
Study Population
Design
Australia (1997)
Case Control Study
144 cases, 144 controls
Finland (2001)
Case Control Study
194 cases, 208 controls
Germany (2004)
Case Control Study
278 cases, 666 controls
USA (2004)
Case Control Study
1,122 cases, 2,036 controls
Denmark (2004)
Case Control Study
381 cases, 381 controls
South Asians living in UK
(2004)
Case Control Study
240 cases, 477 controls
Finland (2004)
Case Control Study
206 Cases, 215 Controls
Netherlands (2001)
Prospective study
88 cases, 268 controls
Urine collected 1-9 years prior
to diagnosis
Prospective study
14,275 participants, 417 cases
Prospective study
Levels of enterolactone in
serum obtained from 383
women with palpable cysts at
the time of their first cyst
aspiration. 18 women
subsequently developed breast
cancer.
Clinical trial, looking at the
effects of dietary flaxseed on
tumour markers and urinary
lignan excretion in
postmenopausal patients with
newly diagnosed breast cancer
Intervention Group: 19
Control Group: 13
USA (2004)
Italy (2004)
Canada (2005)
Findings
Reference
Women in the fourth quartile of
enterolactone excretion were at
decreased risk
Women in the fifth quintile of serum
enterolactone showed decreased risk
[37]
Significantly decreased breast
cancer risk with a high intake of the
plant lignan matairesinol but not for
the sum of plant lignans
Pre-menopausal women with the
highest dietary lignan intake had
reduced breast cancer risk. No
association was observed between
lignan intake and postmenopausal
breast cancer
Lower risk for breast cancer with
higher concentrations of serum
enterolactone, restricted almost
entirely to ER-negative breast
tumours.
Lower risk for breast cancer with
highest intake of dietary
phytoestrogens
High serum enterolactone not
associated with a reduced breast
cancer risk
No protective effect with increased
enterolactone excretion
[44]
No protective effect for serum
lignans on breast cancer risk
High serum enterolactone
concentration has a strong protective
effect on breast cancer risk
[49]
Significantly Reduced c-erbB2
expression and an increase in
apoptosis were observed in the
flaxseed, but not in the placebo
group.
[51]
[43]
[45]
[46]
[47]
[48]
[40]
[50]
11
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