Adolescent and adult soy food intake and breast cancer risk:
results from the Shanghai Women’s Health Study1–4
Sang-Ah Lee, Xiao-Ou Shu, Honglan Li, Gong Yang, Hui Cai, Wanqing Wen, Bu-Tian Ji, Jing Gao, Yu-Tang Gao,
and Wei Zheng
ABSTRACT
Background: Soy food is a rich source of isoflavones—a class of
phytoestrogens that has both antiestrogenic and anticarcinogenic
properties.
Objective: The objective was to evaluate the association of adoles-
cent and adult soy food intake with breast cancer risk in a cohort of
73,223 Chinese women who participated in the Shanghai Women’s
Health Study.
Design: A validated food-frequency questionnaire was used to as-
sess usual dietary intake during adulthood and adolescence. After
a mean follow-up of 7.4 y, 592 incident cases of breast cancer were
identified for longitudinal analyses by using Cox regressions.
Results: Adult soy food consumption, measured either by soy pro-
tein or isoflavone intake, was inversely associated with the risk of
premenopausal breast cancer, and the association was highly statis-
tically significant (P for trend , 0.001). The multivariate-adjusted
relative risks (RRs) for the upper intake quintile compared with the
lowest quintile were 0.41 (95% CI: 0.25, 0.70) for soy protein intake
and 0.44 (95% CI: 0.26, 0.73) for isoflavone intake. High intake of
soy foods during adolescence was also associated with a reduced
risk of premenopausal breast cancer (RR: 0.57; 95% CI: 0.34, 0.97).
Women who consumed a high amount of soy foods consistently
during adolescence and adulthood had a substantially reduced risk
of breast cancer. No significant association with soy food consump-
tion was found for postmenopausal breast cancer.
Conclusion: This large, population-based, prospective cohort study
provides strong evidence of a protective effect of soy food intake
against premenopausal breast cancer. Am J Clin Nutr 2009;
89:1920–6.
INTRODUCTION
Ecological and migration studies have suggested that the
marked international variation in breast cancer incidence is largely
due to environmental factors, such as reproductive patterns and
dietary habits (1). The largely null association found for dietary
fat intake and breast cancer risk (2) has shifted the research
interest to other dietary components, such as soy foods and
phytoestrogens (3). Isoflavones are a class of phytoestrogens
abundant in soy foods that structurally and functionally resemble
mammalian estrogens and compete with endogenous estrogens
for estrogen receptors (4). Several experimental studies have
shown that both soy and isoflavones may protect against hor-
mone-related cancers (4, 5). In addition to their antiestrogenic
1920 Am J Clin Nutr 2009;89:1920–6. Printed in USA. Ó 2009 American Society for Nutrition
effect, soy and isoflavones have been shown to have other cancer-
inhibitory properties, including the inhibition of inflammation,
angiogenesis, and cell proliferation and to stimulate the pro-
duction of sex hormone–binding globulin (SHBG) (5).
A recent meta-analysis suggested an overall small, yet sta-
tistically significant, inverse association of soy intake with breast
cancer risk (6). The association appeared to be somewhat
stronger among premenopausal women than among postmeno-
pausal women. However, substantial heterogeneity was found
across the 18 studies included in the meta-analysis (6). Addi-
tional analyses of published studies, mostly case-control studies,
showed that the inverse association between soy food intake and
breast cancer risk was found in 6 of the 8 studies conducted in
Asian women but in only 1 of the 11 studies conducted in white
women (7). Soy food intake in most white populations, however,
remains very low; thus, informative studies would have to be
conducted in Chinese and in other Asian women who consume
a much higher level of soy foods than their white counterparts.
However, 7 of the 8 Asian studies included in the meta-analysis
used a case-control study design, which inevitably suffer from
selection and recall biases (7). The only cohort study included in
the meta-analysis was conducted in Japan and reported a pro-
tective association with breast cancer risk (8). This finding,
however, was contradictory to that reported very recently from
another Japanese cohort study (9). Given the small sample size
of these 2 cohort studies and their inconsistent findings, addi-
tional research is warranted to clarify the association. In 2001
1
From the Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt Univer-
sity School of Medicine, Nashville, TN (S-AL, X-OS, GY, HC, WW, and
WZ); the Department of Epidemiology, Shanghai Cancer Institute, Shanghai,
China (HL, JG, and Y-TG); the Division of Cancer Epidemiology and Ge-
netics, National Cancer Institute, Rockville, MD (B-TJ); and the Department
of Preventative Medicine, Kangwon National University, Gangwon-do,
Korea (S-AL).
2
The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Cancer Institute.
3
Supported by US Public Health Service grant number R01 CA070867
from the National Institutes of Health.
4
Address correspondence to W Zheng, Vanderbilt Epidemiology Center
Institute of Medicine and Public Health, Vanderbilt University School of
Medicine, 2525 West End Avenue, 8th floor, Nashville, TN 37203-1738.
E-mail: wei.zheng@vanderbilt.edu.
Received December 12, 2008. Accepted for publication April 1, 2009.
First published online April 29, 2009; doi: 10.3945/ajcn.2008.27361.
 SOY INTAKE AND BREAST CANCER RISK
we reported from a case-control study that soy food intake
during adolescence was associated with a reduced risk of breast
cancer (10). This inverse association was also reported in
a subsequent case-control study conducted in Asian American
women (11). However, to date, no prospective cohort study
has validated these findings that may have significant im-
plications in breast cancer prevention. In this study, we in-
vestigated the association of soy food intake with breast cancer
risk using data from a prospective cohort study with a focus on
evaluating the joint effect of soy food intake in adolescents and
adults.
SUBJECTS AND METHODS
Participants
Details of the study design and cohort characteristics for the
Shanghai Women’s Health Study (SWHS) have been described
elsewhere (12, 13). Briefly, between 1996 and 2000, 74,942
women aged 40–70 y were recruited from 80,891 eligible
women who resided in 7 urban communities of Shanghai with
a participation rate of 92.6%. Of the 5949 nonparticipants, 2407
refused to participate (3.0%), 2073 were absent during the study
period (2.6%), and 1469 (1.8%) were excluded for other mis-
cellaneous reasons. All participants were interviewed in person
by trained interviewers using a structured questionnaire. The
questionnaire included questions on sociodemographic factors,
diet and lifestyle habits, menstrual and reproductive history,
hormone use, and medical history. Anthropometric measure-
ments, including current weight, height, and circumferences of
the waist and hips, were also taken by using a standard protocol.
The study was approved by the relevant institutional review
boards for human research, and written informed consent was
obtained from all participants.
Dietary assessment
A validated quantitative food-frequency questionnaire (FFQ)
was used to assess usual dietary intake at the baseline survey and
again at the first follow-up survey, which was conducted ’2–3 y
after the baseline survey. The second FFQ survey was completed
for 92% of cohort members who were alive at the time of the
survey. The FFQ covered virtually all soy foods consumed in
urban Shanghai, including soy milk, tofu, soy products other than
tofu, dried soybeans, soybean sprouts, and fresh soybeans (12,
13). During the in-person interview, each participant was first
asked how often, on average, during the 12 mo preceding the
interview she had consumed a specific food or food group (the
possible responses were daily, weekly, monthly, yearly, or
never), followed by a question on the amount consumed per unit
of time. For seasonal foods such as fresh soybeans, participants
were asked to describe their consumption during each season in
which the food was available. Energy and nutrient intakes, in-
cluding soy protein and isoflavone intakes, were calculated by
multiplying the amount of the food consumed by the nutrient
content per gram of the food, as obtained from the Chinese Food
Composition Tables (14). The correlation coefficient was 0.40
for usual soy protein intake assessed at baseline compared with
that assessed at the second FFQ survey. The FFQ was validated
against the averages of multiple 24-h dietary recalls in a
1921
validation study including ’200 women (13). The correlation
coefficients between intakes derived from the FFQ and the
averages of multiple 24-h recalls were 0.59–0.66 for macro-
nutrients, 0.41–0.59 for micronutrients, 0.41 for soy food, and
0.41–0.66 for other major food groups (12). Dietary intake
during adolescence (between the ages of 13 and 15 y) was as-
certained by using a brief FFQ, including 19 raw food items or
groups, and the following soy food items were included: 1) soy
milk, 2) tofu and other soy products, 3) dry soybeans, and 4)
fresh legumes, including soy beans. Information on the intake of
these soy food items was used to derive the intakes of soy
protein and soy isoflavones during adolescence. A similar
questionnaire was used in a previous case-control study of breast
cancer in Shanghai (10). The correlation coefficient was 0.25
(P , 0.001) between soy protein intake during adulthood and
soy protein intake during adolescence.
Ascertainment of breast cancer cases
The cohort is followed by a combination of active biennial
surveys and periodic linkage with a database maintained by the
Shanghai Cancer Registry and the Shanghai death certificate
registry. The response rates for the first (2000–2002), second
(2002–2004), and third (2004–2007) in-person follow-up surveys
were 99.8%, 98.7%, and 96.7%, respectively. Annual record
linkage of cohort member information with the cancer and death
certificate registries is conducted to ensure a timely and complete
ascertainment of new cancer cases and all deaths in the study
cohort. All possible matches are checked manually and verified
through home visits. Copies of medical charts from hospitals
where cancers were diagnosed are obtained to verify the di-
agnosis and to collect detailed information on the pathologic
characteristics of tumors.
Statistical analysis
For this study, we excluded women with a history of cancer
(n ¼ 1576) at baseline, women who reported extreme total en-
ergy intake (,500 or 3500 kcal/d, n ¼ 124), and women who
were lost to follow-up (n ¼ 8) shortly after recruitment, which
resulted in a total of 73,225 women for the present study.
Two approaches were used to define usual soy food intake
during adulthood. The first approach simply used the intake
assessed at baseline, whereas the other used the average intake
derived from 2 FFQs, administered at baseline and the first
follow-up survey. The latter approach, also termed as the cu-
mulative average method, has been reported to improve the
assessment of usual dietary intake and is now commonly used in
cohort studies that have data from repeat dietary assessments
(15–18). Some women developed cancer, diabetes, myocardial
infarction, or stroke during the period between the baseline and
first follow-up surveys. It is possible that some of these women
may have modified their dietary habits after disease diagnosis;
therefore, for women who had any of these outcomes during this
period, information from the baseline FFQ was used to define
usual soy food intake.
Study participants were divided into quintiles according to
their soy intake level. The lowest quintile served as the reference
group. Relative risks (RRs) and 95% CIs associated with soy
intake were estimated by using the Cox proportional hazards
1922 LEE ET AL
regression model (19). Entry time was defined as age at en-
rollment, and exit time was defined as age at cancer diagnosis or
age at censoring due to death or loss to follow-up. The date of
last follow-up was set as 31 December 2005 for study partic-
ipants whose last in-person contact occurred before 31 De-
cember 2005, 6 mo before the most recent record linkage for the
present version of the data set, to allow for delay in records
processing. To control for confounding by age or birth cohort or
any possible interaction between the 2, we used age as the time
scale in the proportional hazards regression model and stratified
the model on birth cohort (in 5-y intervals) (20). Covariates
included in the model were education, physical activity, age at
first live birth, body mass index, season of recruitment, family
history of breast cancer, and total energy intake. The linear trend
was evaluated by modeling categorical intake variables as or-
dinal variables in the model.
To evaluate any modifying effect of menopause on soy intake,
the analyses were further stratified by menopausal status. In-
formation on menopausal status was updated during the follow-
up surveys and treated as a time-varying variable in the analyses.
In addition, the combined effect of soy intake during adolescence
and adulthood was evaluated. For this analysis, soy food con-
sumption was measured by soy protein intake and categorized by
tertile distribution to improve the stability of point estimates. The
likelihood ratio test was used to evaluate potential multiplicative
interactions of 2 study variables by comparing the models with
and without the cross product terms of these variables. All sta-
tistical tests were based on 2-sided probability. Statistical anal-
yses were carried out by using SAS version 9.1 (SAS Institute,
Cary, NC).
RESULTS
Over a mean follow-up time of 7.4 y (540,156 person-years),
594 incident cases of breast cancer were identified. The mean
(6SD) age at diagnosis was 52.1 6 9.06 y. Significant differences
in cases and noncases were found for education, usual occupa-
tion, and all established breast cancer risk factors evaluated in the
study (Table 1). Participants in the higher quintile of soy protein
intake were more likely to be older, to have higher body mass
indexes and waist-to-hip ratios, and to have higher intakes of
total energy, fruit, vegetables, and meat than did women with
lower soy intakes (Table 1). No apparent association was found
for soy food intake and menstrual and reproductive characteristics.
Very few women in this cohort were regular alcohol drinkers
(1.9%), cigarette smokers (2.4%), or hormone replacement
therapy users (3.9%).
The association of breast cancer with usual intake of soy
protein or isoflavones assessed using either the baseline FFQ
(baseline) or the average of the 2 FFQs administered at baseline
and the first follow-up survey (average) is shown in Table 2.
Overall, soy protein and isoflavone intakes were inversely as-
sociated with the risk of breast cancer, although the trend tests
were not statistically significant. Analyses stratified by meno-
pausal status showed an inverse dose-response association of soy
protein or isoflavone intake with breast cancer risk among pre-
menopausal women by using data from either the baseline FFQ
or the average of the 2 FFQs, although the latter approach
showed a stronger association. No apparent association was
observed between soy food intake and postmenopausal breast
cancer. Excluding women who reported a change in eating
habits during the 5 y preceding study recruitment did not change
the pattern of association (data not shown in table). Further
adjustment for other dietary factors, such as the consumption of
red meat, fruit, vegetables, and carotenoids, did not materially
change the soy and breast cancer association (data not shown).
A similar association pattern was observed between soy food
intake during adolescence and breast cancer risk (Table 3). In
particular, a 43% reduced risk (95% CI: 0.34, 0.97) of pre-
menopausal breast cancer was found among those whose soy
food intake during adolescence was in the highest intake group.
However, the test of linear trend was only of borderline signif-
icance (P ¼ 0.061). In postmenopausal women, a slight positive
association was observed between breast cancer risk and ado-
lescent soy food intake. When soy intake during adulthood and
adolescence were both included in the same model, little change
was seen in the risk estimates associated with adult soy intake,
whereas the inverse association with adolescent soy intake was
attenuated (data not shown). Further analysis of the combined
effect of soy protein intake in adolescence and in adulthood on
premenopausal breast cancer risk was carried out, and the results
are presented in Table 4. High soy food intake during adoles-
cence or adulthood alone was each related to a reduced risk of
premenopausal breast cancer. Women in the highest tertile of
soy protein intake in both adolescence and adulthood had the
greatest decrease in relative risk compared with women in the
lowest tertile of soy protein intake at both of these time points
(RR: 0.41; 95% CI: 0.22, 0.75).
DISCUSSION
In this population-based cohort study, we found that high soy
food intake was associated with a reduced risk of breast cancer
among premenopausal women. Women who consumed a high
level of soy food consistently during adolescence and adulthood
had a substantially reduced risk of breast cancer. These results
suggest that soy food intake may reduce the risk of breast cancer,
and this inverse association may explain some of the low in-
cidence of breast cancer observed in China and several other
Asian countries.
Menopause is a milestone in a woman’s life, resulting in
dramatic changes in levels and production sites of estrogen.
In premenopausal women, estrogen is predominantly produced in
the ovaries, and the concentrations are high. After menopause,
endogenous estrogen is primarily produced in adipose tissue (21–
23), and concentrations of estrogen are substantially lower than
in premenopausal women. Soy isoflavones, a group of phy-
toestrogens that are structurally similar to mammalian estrogen
17b-estradiol, have been shown to exert agonist or antagonist
effects on various estrogen target tissues (3–5). Isoflavones, by
competing with estrogen in binding estrogen receptors, may
exert antiestrogenic effects in high estrogen environments, such
as that in premenopausal women, reducing the risk of breast
cancer. Several intervention studies have shown that a high di-
etary intake of soy products decreased serum estradiol concen-
trations in premenopausal women (24–26). Another study found
that soy consumption increased menstrual cycle length and re-
duced the level of luteinizing hormone and follicle-stimulating
hormone, a change that may reduce the risk of breast cancer
(27). On the other hand, under a low estrogen environment, such
 SOY INTAKE AND BREAST CANCER RISK 1923
TABLE 1
Soy food intake by quintile (Q) and by selected demographic characteristics and known risk factors for breast cancer in the Shanghai Women’s Health Study1
Soy protein intake

Breast cancer Noncases P Q1 Q2 Q3 Q4 Q5 P

cases (n ¼ 594) (n ¼ 72,631) value (4.87) (4.88–7.11) (7.12–9.48) (9.49–12.82) (.12.82) value
Age at baseline (y) 52.1 6 9.062 52.0 6 9.06 0.29 51.5 6 9.43 51.4 6 9.03 51.8 6 8.93 52.3 6 8.91 53.1 6 8.87 ,0.001
Education (%)3
Elementary school 14.2 21.4 22.9 18.8 18.8 19.0 20.5
Middle school 32.4 37.2 19.5 20.3 20.2 20.2 19.8
High school 25.2 27.9 19.1 20.3 20.4 21.5 19.7
College 18.2 13.5 ,0.001 18.7 20.5 20.5 20.0 20.3 ,0.001
Income, whole family (yuan)
,10,000 13.6 16.1 21.2 18.7 18.4 19.5 22.2
10,000–19,999 39.1 38.2 19.4 20.0 20.1 20.1 20.4
20,000–29,999 27.9 28.1 20.3 20.2 20.3 20.3 18.9
30,000 19.4 17.5 0.33 19.7 21.0 20.8 19.8 18.8 ,0.001
Occupation
Professional/technical 39.5 28.5 18.7 20.3 20.5 20.5 20.0
Clerical/service 20.9 20.8 ,0.001 20.8 20.2 19.8 19.3 19.9
Manufacturing/construction 39.5 50.7 20.3 19.8 19.8 20.0 20.1 ,0.023
Regular exercise (%)3 67.3 64.9 0.219 15.6 18.0 20.1 21.8 24.5 ,0.001
(MET/wk) 12.3 6 11.70 13.6 6 14.68 0.209 12.7 6 12.9 12.3 6 13.7 13.2 6 14.8 13.7 6 14.5 15.4 6 16.1 ,0.001
Age at menarche (y) 14.8 6 1.81 14.9 61.74 ,0.01 15.0 6 1.76 14.9 6 1.73 14.9 6 1.71 14.9 6 1.75 14.9 6 1.75 ,0.001
Age at menopause 49.3 6 4.52 48.6 6.34 ,0.001 48.4 6 4.44 48.4 6 4.32 48.6 6 4.28 48.7 6 4.29 48.7 6 4.29 ,0.001
Age at first live birth (y) 26.4 6 4.08 25.6 6 4.13 ,0.001 25.6 6 4.11 25.8 6 4.09 25.7 6 4.04 25.5 6 4.16 25.2 6 4.21 0.393
Nulliparous (%)3 4.2 3.3 0.205 20.1 19.5 18.3 20.2 22.0 0.131
Positive breast cancer family 3.5 1.8 ,0.01 17.4 19.1 20.2 22.2 21.1 0.006
history (%)3
BMI (kg/m2) 24.3 6 3.40 24.0 6 3.42 0.02 23.6 6 3.46 23.8 6 3.36 23.9 6 3.37 24.2 6 3.38 24.5 6 3.47 ,0.001
Waist-to-hip ratio 0.81 6 0.05 0.81 6 0.05 0.09 0.809 6 0.054 0.810 6 0.054 0.810 6 0.053 0.812 6 0.053 0.815 6 0.054 ,0.001
Total energy intake (kcal/d) 1656 6 339 1642 6 346 0.21 1449 6 300.8 1555 6 294.3 1630 6 302.1 1710 6 315.0 1866 6 363.1 ,0.001
Total fruit and vegetable 526 6 250 506 6 238 0.10 403 6 204.5 460 6 208.8 498 6 215.3 542 6 225.8 628 6 269.3 ,0.001
intake (g/d)
Total meat intake (g/d) 90.7 6 42.4 91.1 6 45.4 0.69 75.1 6 40.3 85.4 6 40.5 91.3 6 41.7 97.6 6 44.7 105.8 6 52.4 ,0.001
1
MET, metabolic equivalent.
2
Mean 6 SD (all such values).
3
Frequency.

as that among postmenopausal Chinese women who have
a much lower estrogen concentration than their counterparts in
Western society, soy phytoestrogens may exert their estrogenic
effect, compromising other anticancer properties of soy foods.
Isoflavones have also been shown to have many other bi-
ological effects that potentially reduce breast cancer risk, in-
cluding the inhibition of epidermal growth factor receptor
tyrosine kinase activity, inhibition of topoisomerase II activity,
arrest of cell cycle progression at the G2-M transition, induction
of apoptosis, antioxidant properties, modification of eicosanoid
metabolism, and inhibition of angiogenesis (5). Some studies
have also shown increased ratios of urinary 2-hydroxy to 16a-
hydroxy and 2-hydroxy to 4-hydroxy estrogens associated with
soy intake (28, 29), which suggests a reduced formation of
genotoxic and potentially carcinogenic estrogen metabolites.
Although cumulative evidence strongly supports cancer-
inhibitory effects of soy and certain soy constituents, some studies
also showed adverse effects of these groups of foods. In a mouse
study, soy intake was shown to increase spontaneous mammary
gland tumors (30). In another study, a 2-wk supplement of soy
protein given to women with benign or malignant breast disease
was found to have estrogenic effects in breast tissue (31). It is
possible that the overall effect of soy foods and soy constituents
on breast carcinogenesis may depend on other factors, such as
an individual’s endogenous estrogen concentration, as suggested
in our study for an inverse association seen in premenopausal
women but not in postmenopausal women. A recent meta-
analysis of 18 epidemiologic studies (6) found an overall inverse
association between soy intake and breast cancer risk. Among
the 10 studies that performed analyses stratified by menopausal
status, soy consumption was more strongly associated with
breast cancer in premenopausal women than in postmenopausal
women. A substantial heterogeneity among postmenopausal
women, however, was suggested (6). A recent report from a co-
hort of 37,643 British women that investigated the association of
a vegetarian diet and isoflavone intake with breast cancer risk
found no evidence of an association between dietary isoflavone
intake and breast cancer risk among either pre- or postmenopausal
women (32). The most recent report from the Japan Collaborative
Cohort study also showed no association between intake of tofu,
boiled beans, or miso soup and the risk of breast cancer for
women who were postmenopausal at baseline recruitment (9).
This is contrary to an earlier report from Japan, which showed
a protective effect of soy on breast cancer risk among post-
menopausal women (8), and to a recent report from a nested case-
control study, in which an inverse association between plasma
isoflavone concentrations and breast cancer risk was observed
(33). The sample size for both studies, however, was small (8, 33).
1924 LEE ET AL
TABLE 2
Soy food intake and breast cancer risk by quintile (Q) in the Shanghai Women’s Health Study
RR (95% CI)1

Q1 Q2 Q3 Q4 Q5 P for trend
All women (594 breast
cancer cases)
Soy protein (baseline) 1.00 0.97 (0.75, 1.25) 0.88 (0.68, 1.15) 1.05 (0.81, 1.35) 0.86 (0.65, 1.13) 0.499
Isoflavones (baseline) 1.00 0.92 (0.71, 1.19) 0.96 (0.75, 1.24) 1.00 (0.77, 1.29) 0.86 (0.65, 1.13) 0.514
Soy protein (average) 1.00 1.00 (0.78, 1.29) 0.86 (0.67, 1.12) 0.85 (0.65, 1.11) 0.89 (0.66, 1.15) 0.158
Isoflavones (average) 1.00 0.87 (0.67, 1.12) 1.02 (0.80, 1.30) 0.77 (0.58, 1.00) 0.81 (0.61, 1.07) 0.091
Premenopausal women
(305 breast cancer
cases)2
Soy protein (baseline) 1.00 0.97 (0.70, 1.35) 0.83 (0.58, 1.18) 0.93 (0.65, 1.31) 0.68 (0.45, 1.02) 0.093
Isoflavones (baseline) 1.00 0.85 (0.61, 1.18) 0.89 (0.64, 1.25) 0.75 (0.53, 1.08) 0.65 (0.43, 0.97) 0.034
Soy protein (average) 1.00 0.79 (0.54, 1.15) 0.59 (0.39, 0.91) 0.62 (0.40, 0.95) 0.41 (0.25, 0.70) ,0.001
Isoflavones (average) 1.00 0.66 (0.44, 0.98) 0.80 (0.55, 1.18) 0.48 (0.30, 0.77) 0.44 (0.26, 0.73) ,0.001
Postmenopausal women
(289 breast cancer
cases)3
Soy protein (baseline) 1.00 0.98 (0.66, 1.47) 0.98 (0.66, 1.46) 1.23 (0.84, 1.81) 1.08 (0.72, 1.61) 0.396
Isoflavones (baseline) 1.00 1.04 (0.69, 1.56) 1.11 (0.74, 1.66) 1.38 (0.94, 2.02) 1.16 (0.78, 1.74) 0.191
Soy protein (average) 1.00 1.21 (0.87, 1.69) 1.11 (0.80, 1.56) 1.07 (0.76, 1.50) 1.22 (0.87, 1.71) 0.504
Isoflavones (average) 1.00 1.05 (0.76, 1.47) 1.22 (0.88, 1.68) 1.00 (0.71, 1.40) 1.09 (0.78, 1.52) 0.800
1
Relative risks (RRs) and 95% CIs were derived from Cox regression analyses, compared with the lowest quintile, and adjusted for age, education,
physical activity, age at first live birth, BMI, season of recruitment, family history of breast cancer, and total energy intake. Median values (and cutoffs) for the
lowest to the highest quintile of soy protein intake (g/d) are as follows: 3.53 (4.87), 6.03 (4.88, 7.11), 8.23 (7.12, 9.48), 10.93 (9.49, 12.83), and 16.02
(12.84). The corresponding numbers for soy isoflavones (mg/d) are as follows: 11.23 (15.93), 20.06 (15.94, 23.88), 27.93 (23.89, 32.43), 37.57 (32.44,
44.23), and 54.97 (44.24).
2
Mean age at cancer diagnosis was 47.9 y.
3
Mean age at cancer diagnosis was 58.6 y.

In vivo studies have consistently shown that prepubertal or 15 y, when most of the study participants started puberty. The
pubertal exposure to genistein either via injections or feeding mean age of menarche was 14.9 y. We previously reported that
reduces the incidence and/or multiplicity of chemically induced soy food intake during this period was inversely related to the
mammary tumors in experimental animals (34). To evaluate the risk of breast cancer among Chinese women (10). This associ-
effect of prepubertal and pubertal soy exposure on breast cancer ation was subsequently replicated in a study of Asian American
risk, we assessed usual soy food intake during the ages of 13 to women (11). These results raise the question as to whether soy
TABLE 3
Association between soy food intake during adolescence and breast cancer risk by quintile (Q) in the Shanghai Women’s Health Study
RR (95% CI)1

Groups Q1 Q2 Q3 Q4 Q5 P for trend

All women (594 breast
cancer cases)
Soy protein 1.00 0.92 (0.71, 1.19) 1.07 (0.83, 1.38) 0.98 (0.76, 1.27) 0.97 (0.75, 1.27) 0.970
Isoflavones 1.00 1.07 (0.82, 1.39) 1.04 (0.80, 1.36) 1.12 (0.86, 1.45) 1.19 (0.91, 1.55) 0.196
Premenopausal
(305 breast
cancer cases)
Soy protein 1.00 0.78 (0.52, 1.18) 0.87 (0.58, 1.31) 0.77 (0.50, 1.18) 0.57 (0.34, 0.97) 0.061
Isoflavones 1.00 0.91 (0.59, 1.40) 0.76 (0.48, 1.18) 0.79 (0.51, 1.24) 0.89 (0.57, 1.40) 0.452
Postmenopausal
(289 breast
cancer cases)
Soy protein 1.00 1.01 (0.72, 1.41) 1.22 (0.88, 1.68) 1.13 (0.82, 1.56) 1.20 (0.87, 1.65) 0.200
Isoflavones 1.00 1.17 (0.83, 1.64) 1.23 (0.88, 1.72) 1.33 (0.96, 1.85) 1.38 (1.00, 1.91) 0.038
1
Relative risks (RRs) and 95% CIs were derived from Cox regression analyses, compared with the lowest quintile, and adjusted for age, education,
physical activity, age at first live birth, BMI, season of recruitment, family history of breast cancer, total energy intake, and total fruit and vegetable intakes
during adolescence. Median values (and cutoffs) for the lowest to the highest quintile of soy protein intake (g/d) are as follows: 1.73 (2.76), 3.76 (2.77, 4.70),
5.81 (4.71, 6.95), 8.86 (6.96, 11.32), and 15.16 (11.33). The corresponding numbers for soy isoflavones (mg/d) are as follows: 4.31 (7.34), 10.04 (7.35,
12.82), 15.99 (12.83, 19.43), 24.11 (19.44, 31.28), and 42.26 (31.28).
 SOY INTAKE AND BREAST CANCER RISK
TABLE 4
Joint effect of soy food intake during adulthood and adolescence on breast cancer risk among premenopausal women in the Shanghai Women’s Health Study1
,6.39
Soy protein intake in adolescence n3 RR (95% CI)4
4.00 91 1.00 (reference)
4.01–8.04 76 0.96 (0.62, 1.49)
8.05 40 0.62 (0.33, 1.19)
1
Low, middle, and high intakes were defined after division by tertile of each intake of soy protein during adolescence and adulthood. P for interaction ¼
0.017.
2
Median values for the lowest to the highest tertile of soy protein intake (g/d) are as follows: 4.46, 8.23, and 13.66 during adulthood and 2.43, 5.75, and
12.17 during adolescence.
3
Number of breast cancer cases.
4
Relative risks (RRs) and 95% CIs were derived from Cox regression analyses and adjusted for age, education, physical activity, age at first live birth,
BMI, season of recruitment, family history of breast cancer, total energy intake, and total fruit and vegetable intakes during adolescence and at recruitment.
food intake during adolescence, a critical window for breast
development, is the primary mechanism by which soy exerts its
cancer-preventive effect on the breast. In our study, despite the
fact that a high consumption of soy foods during both adoles-
cence and adulthood was associated with the largest reduction in
breast cancer risk; high consumption of soy food in adolescence
or adulthood alone was each inversely associated with risk.
Whereas laboratory studies have suggested that the mechanisms
by which soy intake exerts its effect may differ during ado-
lescence (eg, promotion of terminal bud differentiation) and
adulthood (eg, competition with estrogen receptors, stimulation
of SHBG syntheses, antioxidative, and antiangiogenesis), the
reasons for the inverse association of adolescent soy intake with
premenopausal but not with postmenopausal breast cancer are
unclear, and further investigations are warranted.
As with any observational study, errors in assessing usual
dietary intake were a potential concern in our study. This type of
error, however, is likely to be nondifferential between cases and
noncases in a prospective cohort study and thus does not explain
the inverse association observed in our study. We carefully
designed the questionnaire to include virtually all soy foods that
are commonly consumed in Shanghai. The validation study,
implemented as part of the SWHS, indicates that the FFQ used
in the SWHS has good validity and reliability in assessing usual
soy food intake in adulthood. In addition to the baseline survey,
dietary information was also collected at the first follow-up
survey implemented 2–3 y after the baseline survey, which helps to
reduce random errors and improves dietary assessment.
Loss to follow-up can introduce selection biases. This, however,
was not a major concern in the present study, because the response
rates at follow-up are very high. High soy food intake could be
related to certain lifestyles that may be associated with reduced risks
of breast cancer. However, the inverse association between soy food
intake and breast cancer risk remained after a wide range of
sociodemographic, lifestyle, and known risk factors for breast cancer
were controlled for. The statistical power in our study was low for
some subgroup analyses. With an extended follow-up of this cohort
and data from additional FFQ surveys, we should be able to re-
evaluate the association of soy food intake with breast cancer risk in
the future with a larger sample size and improved exposure data.
In summary, in a large prospective cohort study conducted
among Chinese women, we found that high soy food intake was
1925
Soy protein intake in adulthood2
6.39–10.40 10.41
n3 RR (95% CI)4 n3 RR (95% CI)4
56 0.57 (0.32, 0.99) 32 0.57 (0.30, 1.08)
64 0.56 (0.33, 0.94) 70 0.59 (0.34, 1.03)
74 0.67 (0.39, 1.15) 91 0.41 (0.22, 0.75)
inversely associated with premenopausal breast cancer risk.
These results are consistent with the cancer-inhibitory effects of
soy isoflavones, which suggests that an increase in soy food
intake can reduce the risk of breast cancer.
We thank the research staff and participants of the SWHS and Brandy Sue
Venuti and Bethanie Hull for technical assistance in the preparation of this
manuscript.
The authors’ responsibilities were as follows: WZ, X-OS, Y-TG, and GY:
conceived and directed the study; S-AL, HC, and WW: performed statistical
analyses; S-AL, X-OS, and WZ: drafted the manuscript; and HL, B-TJ, and
JG: contributed to data collection and reviewed the manuscript. WZ is the
principal investigator for the study. None of the authors had any financial
conflicts of interest.
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