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Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
Int. J. Cancer: 75, 439–443 (1998)
r 1998 Wiley-Liss, Inc.
EFFECT OF WHEAT BRAN FIBER ON THE DEVELOPMENT OF MAMMARY
TUMORS IN FEMALE INTACT AND OVARIECTOMIZED RATS TREATED
WITH 7,12-DIMETHYLBENZ(A)ANTHRACENE AND IN MICE
WITH SPONTANEOUSLY DEVELOPING MAMMARY TUMORS
Maija H. ZILE1*, Clifford W. WELSCH2 and Margaret A. WELSCH1
of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, USA
2Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
1Department
We examined the effect of consumption of graded increases of dietary fiber (soft white wheat bran) on the
development of mammary gland carcinomas in intact female
Sprague-Dawley rats during the promotion stage of carcinogenesis, induced with 7,12-dimethylbenz(a)anthracene
(DMBA). The percent of rats with mammary carcinomas, the
total number of mammary carcinomas and the mean number
of mammary carcinomas per rat were reduced significantly
at all fiber levels examined compared to rats fed a control
diet. Inclusion of 9.6% fiber in the diets of ovariectomized rats
that had been treated with a single i.v. dose of 2.5 mg
DMBA/100 g body weight 2 weeks prior to removal of the
ovaries resulted in a significant decrease of carcinomatous
and benign mammary tumors compared to ovariectomized
rats fed a control diet. Development of spontaneous mammary carcinomas in virgin C3H/HeOuJ female mice and
growth of a transplantable mammary gland tumor in such
mice were reduced by inclusion of 9.6% fiber in the diet, a
reduction that was significant or just barely missed significance, depending on the source of the fiber. Our observations
provide evidence that inclusion of soft white wheat bran in
the diet is effective in the suppression of mammary gland
tumorigenesis in an array of experimental animal models. Int.
J. Cancer 75:439–443, 1998.
r 1998 Wiley-Liss, Inc.
Breast cancer has a mortality rate of over 50% and is among the
major causes of death in women worldwide (Stoll, 1987). While the
exact cause(s) and the molecular mechanism(s) involved are not
clear, most of the evidence available links breast cancer to the
function of ovaries, i.e., the ovarian hormones estrogen and
progesterone (Kelsey, 1979; Lubin et al., 1982; Helmrich et al.,
1983; reviewed by Sheikh et al., 1994–1995). Epidemiological
studies suggest that diet may play an important role in breast cancer
(Haenszel and Kurihara, 1968; Gray et al., 1979; Persky et al.,
1992). High fat intake has been linked generally to an increase in
breast cancer risk (reviewed by Willett and Hunter, 1993), while
epidemiological evidence indicates that fiber may have a protective
role (reviewed by Rose, 1990). The major support for the latter
hypothesis comes from the observation that in Finland, where fat
intake is high and similar to that in the United States but fiber intake
is much higher than that in the United States, breast cancer
incidence is considerably lower than in the United States (reviewed
by Cohen et al., 1991). However, a prospective cohort study found
no significant association between breast cancer risk and fiber
intake (Verhoeven et al., 1997). Nutritional epidemiological investigations clearly can provide only clues to the dietary factors that
might participate in breast cancer etiology. Experimental studies
are needed to establish a clear relationship between the development of mammary cancer and dietary fiber. Only limited experimental data are available on the potentially beneficial effect of dietary
fiber in the prevention of mammary cancer in experimental
animals.
Cohen et al. (1991) reported that feeding a diet high in fiber (soft
white wheat bran) to female F344 rats suppressed the promotional
stage of N-methyl-N-nitrosourea (MNU)-induced mammary gland
tumorigenesis. The percent of rats with mammary carcinomas, the
total number of mammary carcinomas and the mean number of
mammary carcinomas per rat were reduced significantly ( p , 0.01)
in the fiber-fed rats. This significant reduction in mammary gland
tumorigenesis was observed in the rats fed a high-fat diet; in
animals fed a low-fat diet, no significant effect of dietary fiber on
mammary gland tumorigenesis was observed. During the same
year, Arts et al. (1991) reported that high levels of dietary fiber
(wheat bran) fed to female F344 rats commencing 3 weeks before
MNU treatment and for the duration of the study resulted in a
significant reduction ( p , 0.01) in mean mammary carcinoma
weight; however, the percent of rats with mammary carcinomas,
the mean number of mammary carcinomas per rat and the mean
latency period of mammary carcinoma appearance were not
influenced significantly by the high-fiber diet. Similarly, Fisher et
al. (1985) reported the lack of a significant effect of high levels of
dietary fiber (white bread, wholemeal bread or bran) on the
spontaneous development of mammary fibroadenomas or mammary carcinomas in female Wistar rats fed the fiber-supplemented
diets throughout their life-span. From these reports, it is reasonable
to conclude that a suppressive role for dietary fiber in the
development and/or growth of mammary gland tumors in experimental animals has not been established. More research is required
to clarify the role of dietary fiber in reducing the risk of mammary
cancer.
In the studies reported here, we have undertaken to examine
further the potentially beneficial role of dietary fiber in the
suppression of mammary cancer in carcinogen-treated female rats.
We also address the aspect of dose responsiveness. In addition, we
examined the effect of dietary fiber in ovariectomized rats to test
the ‘‘estrogen hypothesis,’’ which has been used to explain the
mechanism by which dietary fiber suppresses experimental mammary gland tumorigenesis and has been implied when interpreting
epidemiological studies (Rose, 1990; Adlercreutz et al., 1986). If
dietary fiber can significantly suppress the development of mammary cancers in ovariectomized animals, i.e., in animals that
develop ovarian hormone-independent mammary tumors, it may be
concluded that dietary fiber can act via a mechanism independent
of estrogen activities. Furthermore, we report on the effect of
dietary fiber on the development of spontaneous mammary cancer
using C3H mice, the most commonly used animal model for the
study of spontaneous mammary tumorigenesis. Data also are
presented on the effect of dietary fiber on a transplantable murine
mammary cancer cell line.
Contract grant sponsor: Kellogg Corporation.
*Correspondence to: Department of Food Science and Human Nutrition,
234 Trout Bldg., Michigan State University, East Lansing, MI 48824, USA.
Fax: (517) 353-8963. E-mail: zile@pilot.msu.edu
Received 15 July 1997
ZILE ET AL.
440
TABLE II – DIET COMPOSITION FOR MICE
MATERIAL AND METHODS
Animals and diets
Female Sprague-Dawley rats were purchased from Harlan
Sprague-Dawley (Indianapolis, IN). Animals were housed 3 per
cage in plastic boxes in an environmentally controlled room (light
14 hr, temperature 24°C, relative humidity 40%). Body weights
were recorded weekly. Water and diets were provided ad libitum.
The composition of the diets is described in Table I. Two sources of
fiber were used: soft white wheat bran from the American
Association of Cereal Chemists (St. Paul, MN; Minnesota fiber)
and soft white wheat bran from King Milling Co. (Lowell, MI;
Michigan fiber). The ‘‘low-fiber’’ group received the Minnesota
fiber at 5% of the diet. ‘‘Intermediate-fiber’’ groups received the
Minnesota fiber or the Michigan fiber at 9.6% of the diet. The
‘‘high-fiber’’ group received the Minnesota fiber at 17.5% of the
diet.
Female virgin C3H/HeOuJ mice were obtained from the Jackson
Laboratory (Bar Harbor, ME). Mice were housed in plastic boxes, 5
per box, in an environmentally controlled room. Body weight was
recorded weekly; water and diets were provided ad libitum. The
composition of the diets is given in Table II. In these studies, the
Minnesota fiber and the Michigan fiber were examined only at the
intermediate level, i.e., 9.6% of the diet.
TABLE I – DIET COMPOSITION FOR RATS
Diet
Control
Fat (corn oil)
Casein
d,l-methionine
Dextrose
Sucrose
AIN mineral mix
AIN vitamin mix
Celufil
Fiber
Total
Low-level fiber
Fat (corn oil)
Casein
d,l-methionine
Dextrose
Sucrose
AIN mineral mix
AIN vitamin mix
Celufil
Fiber
Total
Intermediate-level fiber
Fat (corn oil)
Casein
d,l-methionine
Dextrose
Sucrose
AIN mineral mix
AIN vitamin mix
Celufil
Fiber
Total
High-level fiber
Fat (corn oil)
Casein
d,l-methionine
Dextrose
Sucrose
AIN mineral mix
AIN vitamin mix
Celufil
Fiber
Total
% Weight
kcal/rat/day
g/rat/day
20.00
20.17
0.35
33.08
16.09
4.13
1.18
5.00
—
100.00
17.66
7.91
0.14
12.98
6.31
—
—
—
—
45.00
1.96
1.98
0.04
3.25
1.58
0.41
0.12
0.49
—
9.83
18.94
19.13
0.39
31.40
15.27
3.96
1.16
4.73
5.00
99.98
17.64
7.92
0.16
13.00
6.32
—
—
—
—
45.04
1.96
1.98
0.04
3.25
1.58
0.41
0.12
0.49
0.52
10.35
18.05
18.22
0.37
29.90
14.54
3.77
1.10
4.51
9.57
100.03
17.64
7.92
0.16
13.00
6.32
—
—
—
—
45.04
1.96
1.98
0.04
3.25
1.58
0.41
0.12
0.49
1.04
10.87
16.46
16.62
0.34
27.29
13.27
3.44
1.01
4.11
17.46
100.00
17.64
7.92
0.16
13.00
6.32
—
—
—
—
45.04
1.96
1.98
0.04
3.25
1.58
0.41
0.12
0.49
2.08
11.91
Diet
Control
Fat (corn oil)
Casein
d,l-methionine
Dextrose
Sucrose
AIN mineral mix
AIN vitamin mix
Celufil
Fiber
Total
Intermediate-level fiber
Fat (corn oil)
Casein
d,l-methionine
Dextrose
Sucrose
AIN mineral mix
AIN vitamin mix
Celufil
Fiber
Total
% Weight
kcal/mouse/day
g/mouse/day
20.00
20.17
0.35
33.08
16.09
4.13
1.18
5.00
—
100.00
7.06
3.17
0.06
5.19
2.52
—
—
—
—
18.00
0.78
0.79
0.02
1.30
0.63
0.16
0.05
0.20
—
3.93
18.05
18.22
0.37
29.90
14.54
3.77
1.10
4.51
9.57
100.03
7.06
3.17
0.06
5.19
2.52
—
—
—
—
18.00
0.78
0.79
0.02
1.30
0.63
0.16
0.05
0.20
0.41
4.34
Diet components
The components of the diets were as follows: dextrose and
AIN-76 Mineral Mix (Amersham, Arlington Heights, IL); casein
(vitamin-free), sucrose, corn oil and AIN-76 vitamin mix (Dyets,
Bethlehem, PA); celufil (USB, Cleveland, OH).
Rationale for the selection of experimental diets
Rat diets were iso-energetic; each diet provided each rat the
same quantity of fat, protein, dextrose, sucrose, vitamins, minerals
and celufil. Diets were constructed based on an average consumption of 45 kcal/rat/day. Minerals, vitamins, celufil and fiber
(Minnesota fiber or Michigan fiber) were designated as being of
zero caloric value. This is not entirely correct as celufil and the fiber
used in these studies have some caloric value, though it is not
known precisely.
Mouse diets were also iso-energetic; each diet provided each
mouse with the same quantity of fat, protein, dextrose, sucrose,
vitamins, minerals and celufil. Diets were constructed based on an
average consumption of 18 kcal/mouse/day.
Experimental design and methods
Study 1 was designed to determine whether or not graded
increases in dietary fiber consumption (Minnesota fiber) could
suppress the development of 7,12-dimethylbenz(a)anthracene
(DMBA)-induced mammary gland tumorigenesis (promotion stage)
in female Sprague-Dawley rats in a dose-related manner. Female
Sprague-Dawley rats were obtained at 36 days of age and fed the
control diet. At the age of 50 days, all animals were injected i.v.
with a single dose of DMBA (Upjohn, Kalamazoo, MI), 2.5
mg/100 g body weight (bw). At the age of 57 days, animals were
divided into 5 groups, 35 rats/group. One group was continued on
the control diet. The 2nd group was provided a diet containing 5%
Minnesota fiber (low fiber). The 3rd group was provided a diet
containing 9.6% Minnesota fiber (intermediate Minnesota fiber),
while a 4th group received 9.6% Michigan fiber (intermediate
Michigan fiber). The 5th group was provided with 17.6% of
Minnesota fiber in the diet (high fiber). Mammary tumor development was assessed by determining the following parameters:
percent of rats/group with mammary carcinomas and mean number
of mammary carcinomas/rat. All animals were killed at 141 days of
age, 13 weeks after carcinogen treatment.
Study 2 was designed to determine whether or not high levels of
dietary fiber can suppress the development of DMBA-induced
mammary gland tumorigenesis (promotion stage) in female Sprague-
DIETARY FIBER AND MAMMARY TUMORS
Dawley rats ovariectomized 2 weeks after carcinogen treatment.
The mammary carcinomas that develop in ovariectomized rats are
ovarian hormone-independent. This study was designed to examine
the ‘‘estrogen hypothesis’’ as an explanation for the mechanism by
which dietary fiber suppresses experimental mammary gland
tumorigenesis. If dietary fiber can significantly suppress the
development of mammary carcinomas in this model system, it can
be concluded that dietary fiber can act via a mechanism independent of estrogen activities. Female Sprague-Dawley rats were
obtained at 36 days of age and fed the control diet. At the age of 50
days, rats were injected i.v. with a single dose of DMBA, 2.5
mg/100 g bw. At 64 days of age, all rats were bilaterally
ovariectomized. At the age of 71 days, rats were divided into 3
groups, 59 to 60 rats/group. The first group was continued on the
control diet, the second group was fed 9.6% Minnesota fiber in the
diet (intermediate Minnesota fiber) and the third group was fed
9.6% Michigan fiber in the diet (intermediate Michigan fiber).
Mammary tumor development was assessed by determining the
following parameters: percent of rats/group with mammary tumors
and mean number of mammary tumors/rat. The histopathology of
each mammary tumor was determined as in this model system
(DMBA followed by ovariectomy, termination of study 29 weeks
after DMBA treatment) many benign as well as carcinomatous
mammary tumors are being observed. In DMBA-treated intact
female rats, at 13 weeks after DMBA treatment (Study 1), virtually
all of the mammary tumors were carcinomas. All animals were
killed at 253 days of age, 29 weeks after carcinogen treatment.
Study 3 was designed to determine whether or not the 9.6%
dietary fiber level could suppress the development of spontaneous
mammary gland carcinomas in female C3H mice. Virgin female
C3H mice (C3H/HeOuJ) were obtained at the age of 21 days and fed
the control diet for 2 weeks, then divided into 3 groups of 80 mice
each. One group was continued on the control diet, the second
group received 9.6% Minnesota fiber in the diet (intermediate
Minnesota fiber) and the third group was fed a diet with 9.6%
Michigan fiber (intermediate Michigan fiber). Mammary carcinoma development was assessed by determining the following
parameters: percentage of mice in each group with mammary
carcinomas and mean number of mammary carcinomas/mouse. All
animals were killed at 330 days of age, 300 days after the
commencement of feeding the fiber diets. (After this study began,
we were informed by the staff at the Jackson Laboratories that the
activity of the mouse mammary tumor virus [MTV] had recently
and unexpectedly declined substantially in their female virgin
C3H/HeOuJ strain. Thus, as will be seen below, the percent of these
mice with mammary carcinomas, i.e., 24% in the control group, is
reduced sharply from past incidence levels for this age.)
Study 4 was designed to determine if the growth of a transplantable mammary tumor could be suppressed by providing 9.6% fiber
in the diet of host mice. Virgin female C3H/HeOuJ mice were
obtained at the age of 21 days and fed the control diet for 10 days,
after which they were divided in 3 groups of 67 to 75 mice/group
and fed either the control diet or a diet with 9.6% Minnesota fiber
(intermediate Minnesota fiber) or a diet with 9.6% Michigan fiber
441
(intermediate Michigan fiber) for 10 months. Transplantable mouse
mammary tumor cells (ATCC-CRL-1637) were obtained from the
ATCC (Rockville, MD), grown in culture for 2 weeks, harvested
and implanted s.c. (5 3 105 cells/mouse) in the scapular region of
each mouse at 10 months of age. The transplanted mammary tumor
cells were allowed to grow for 1 month, at which time the study
was terminated and the tumors excised and weighed.
Statistical analysis
Mean number of mammary tumors per animal was analyzed by
1-way ANOVA. Mean separations were performed using Duncan’s
multiple range test; x2 analysis was used to determine percent of
animals with mammary tumors. For mean values to be significantly
different, p had to be equal to or less than 0.05.
Detection of mammary tumors
In Studies 1 and 2, mammary tumor palpations began 1 month
after DMBA treatment and were performed bi-weekly until study
termination. When tumors reached 2.0 cm in diameter, tumors were
excised surgically from the lightly anesthetized animal and the
animal was placed back on the experiment. In Study 3, mammary
tumor palpation began at 4 months of age and continued monthly
until termination of study. At the termination of studies, all animals
were killed and palpable as well as non-palpable mammary tumors
were excised.
RESULTS
Effect of dietary fiber on the promotion stage of DMBA-induced
mammary gland tumorigenesis of intact rats
The percent of rats with mammary carcinomas, the total number
of mammary carcinomas and the mean number of mammary
carcinomas per rat are shown in Table III. There was a striking
decrease (44%) in the total number of mammary carcinomas when
rats were fed a diet containing the 9.6% and 17.5% levels of the
Minnesota fiber. Indeed, the mean number of mammary carcinomas per rat was reduced significantly at all levels of fiber tested,
and this reduction was greater when fiber level was increased.
Reductions of mean mammary carcinomas per rat were 22% at the
low (5%) fiber level and 43% and 45% at the medium (9.6%) and
high (17.5%) levels, respectively. While the percentage of rats with
mammary tumors in all fiber-fed groups (89–94%) was numerically less than the controls (100%), the relatively large number of
mammary tumors that developed in each group does not allow for
this parameter to be significant. Feces were collected from 12 rats
in each group every 96 hr. Rats were housed individually in
metabolism cages. Dry fecal weight and fecal volume (not packed)
were increased in a dose-dependent manner as the dietary fiber
content was increased. From a control group level of 61.0 g of dry
feces, this parameter increased by 18% (to 72.3 g), 32% (to 80.3 g)
and 35% (to 82.1 g) when Minnesota fiber was fed at dietary levels
of 5%, 9.6% and 17.5%, respectively. This proportional increase in
fecal dry weight was also evident when calculated per rat per 24 hr.
TABLE III – EFFECT OF WHEAT BRAN FIBER ON DEVELOPMENT OF MAMMARY CARCINOMAS IN INTACT FEMALE
SPRAGUE-DAWLEY RATS TREATED WITH DMBA
Group
Number
of rats
per group
Mean initial
body weight (g)
Mean final body
weight (g)
Rats with
mammary
carcinomas (%)
Total number
of mammary
carcinomas
Mean number
of mammary
carcinomas
per rat (6S.E.)
Control
Low Minnesota fiber
Intermediate Minnesota fiber
High Minnesota fiber
Intermediate Michigan fiber
35
35
35
35
35
194
189
190
192
189
271
265
258
252
250
100
89
94
89
94
203
156
115
113
144
5.8 6 0.81
4.5 6 0.53
3.3 6 0.44
3.2 6 0.43
4.1 6 0.52
All rats were treated with DMBA at 50 days of age. Fiber diets were begun 1 week later and continued
daily for 12 weeks until experiment termination.–1/2p , 0.05.–1/4p , 0.02.–1/3p , 0.01.–1/2/3/4p , 0.001.
ZILE ET AL.
442
TABLE IV – EFFECT OF WHEAT BRAN FIBER ON DEVELOPMENT OF MAMMARY TUMORS IN OVARIECTOMIZED SPRAGUE-DAWLEY RATS TREATED WITH DMBA
Number
Mean
Mean
Rats with Total number Mean number of
Histopathology: total number of mammary tumors
of rats
initial body final body mammary of mammary mammary tumors
per group weight (g) weight (g) tumors (%)
tumors
per rat (6S.E.) Carcinomas Adenomas Adenofibromas Fibromas
Group
Control
Intermediate Minnesota fiber
Intermediate Michigan fiber
60
59
59
194
197
201
362
346
342
681
492
462
1.6 6 0.25
0.8 6 0.13
0.9 6 0.24
94
45
55
606
387
467
188
29
39
1410
511
611
2
—
—
All rats were treated with DMBA at 50 days of age; each rat was ovariectomized at 64 days of age. Fiber diets were begun 1 week after
ovariectomy and continued daily for 26 weeks, at which time the experiment was terminated.–1/2p , 0.001.–3/4p , 0.032.–3/5p , 0.004.–6/7p ,
0.01.–8/9p , 0.002.–10/11p , 0.05.
TABLE V – EFFECT OF WHEAT BRAN FIBER ON SPONTANEOUSLY DEVELOPING MAMMARY CARCINOMAS
IN VIRGIN C3H/HeOuJ MICE
Group
Control
Intermediate Minnesota fiber
Intermediate Michigan fiber
Number of mice
Mean number of
Number
Mean initial
Mean final
with spontaneous
spontaneous
of mice
body
weight
(g)
body
weight
(g)
mammary
mammary
carcinomas
per group
carcinomas (%)
per mouse (6S.E.)
80
80
80
20
19
20
44
44
45
0.26 6 0.064
0.08 6 0.036
0.20 6 0.055
19 (24)1
6 (8)3
14 (18)2
Fiber diets were begun at 1 month of age and continued daily until experiment termination at 11 months
of age.–1/2p , 0.15.–1/3p , 0.001.–4/5p . 0.60.–4/6p , 0.02.
Similarly, fecal volume increased from the control volume of 163
ml to 188 ml, 240 ml and 291 ml, respectively.
Effect of dietary fiber on DMBA-induced mammary gland
tumorigenesis of ovariectomized rats
The percent of rats with mammary tumors, the total number of
mammary tumors, the mean number of mammary tumors per rat
and the tumor histopathology are shown in Table IV. Results
represent 2 experimental groups at the 9.6% (intermediate) dietary
fiber level. With both the Minnesota fiber and the Michigan fiber
there was a significant reduction in the number of rats with
mammary tumors (27% and 32%, respectively), as well as in total
number of mammary tumors (52% and 41%, respectively) and in
mean number of mammary tumors per rat. Histopathological
examination revealed that the majority of mammary tumors in
ovariectomized rats were carcinomas. Ovariectomized rats that had
been provided with 9.6% (intermediate level) of Minnesota fiber
had 36% fewer carcinomas, and rats fed 9.6% (intermediate level)
of the Michigan fiber had 22% fewer carcinomas. The total number
of benign mammary tumors (adenomas, adenofibromas) also was
reduced significantly in the ovariectomized rats fed the fiber diets
compared to control rats. Mean uterine wet weights (g 6 S.E.) in
rats from the ovariectomized controls, the Minnesota fiber group
and the Michigan fiber group were 0.109 6 0.009, 0.131 6 0.015
and 0.112 6 0.012, respectively. These differences were not
significant.
Effect of dietary fiber on spontaneously developing mammary
carcinomas in C3H/HeOuJ mice
The number and percent of mice with mammary carcinomas and
the mean number of spontaneous mammary carcinomas per mouse
are shown in Table V. Results represent 2 experimental groups at
the intermediate (9.6%) dietary fiber level. Both dietary fiber
groups (Minnesota and Michigan) caused a numerical reduction in
both of these parameters of mammary tumorigenesis compared to
control values; only the reduction in tumorigenesis by the Minnesota fiber was significant.
Effect of dietary fiber on growth of transplantable mammary
tumors in C3H/HeOuJ mice
This study represents 2 experimental groups at the intermediate
(9.6%) dietary fiber level and the effect of fiber on the weight of the
transplanted mammary tumors at experiment termination (Table
VI). A statistically significant reduction was observed only in mice
TABLE VI – EFFECT OF WHEAT BRAN FIBER ON GROWTH OF
TRANSPLANTABLE MAMMARY TUMORS IN FEMALE C3H/HeOuJ MICE
Mean weight of transplanted
Number of
per mouse
mice per group mammary(gtumors
6 S.E.)
Group
Control
Intermediate Minnesota fiber
Intermediate Michigan fiber
68
75
67
1.26 6 0.131
1.00 6 0.083
0.81 6 0.092
Fiber diets were begun at 1 month of age and continued daily until
experiment termination at 11 months of age. Transplantable mammary
tumor cells (ATCC-CRL-1637) were implanted s.c. in scapular region
of each mouse at 10 months of age, excised and weighed at experiment
termination at 11 months of age.–1/2p , 0.01.–1/3p , 0.15.
fed the Michigan fiber; Minnesota fiber did not reduce significantly
( p , 0.15) the weight of the transplanted tumors.
DISCUSSION
Since breast cancer is of major consequence to womens’ health,
it is important to examine every potential approach that might lead
to a lowering of the incidence of this disease. Decreasing cancer
risk by modulation of dietary behavior is an attainable goal. The
health benefits of increased dietary fiber intake are generally not
disputed, particularly in regard to bowel health, while the link to
lowering heart disease has not been established clearly (Rimm et
al., 1996; Katan, 1996). Evidence from epidemiological studies
suggests that breast cancer risk also may be lowered by an
increased dietary fiber consumption (Rose, 1990). There are
several studies that have addressed this important question using
controlled experimental animal models (Fisher et al., 1985; Cohen
et al., 1991; Arts et al., 1991), but the overall results have been
inconclusive.
In our studies, we have addressed several questions concerning
the relationship of dietary fiber and mammary tumor development
in experimental animals. One observation is that the total number
of mammary tumors as well as the number of mammary tumors per
rat were numerically decreased as dietary soft white wheat bran
was increased from 5% to 9.6% and 17.5% (Table III). Another
aspect that we addressed concerns the potential mechanism of
action of fiber in suppressing mammary tumor development.
DIETARY FIBER AND MAMMARY TUMORS
Adlercreutz et al. (1975, 1986) have proposed that the lower risk of
breast cancer in women with high fiber intake is related to a lower
level of estrogens in their circulation as a consequence of an
enhanced removal of conjugated estrogens by fiber in the bowel,
with microflora playing an important role in the enterohepatic
recirculation of estrogen (see also Gorbach, 1984; Schultz and
Howie, 1986). Another mechanism proposed by Adlercreutz et al.
(1986) is that dietary fiber may be fermented by microflora in the
bowel to form lignans, which may act as regulators of estrogen
activity. These mechanisms are based on the concept that dietary
fiber suppresses mammary (breast) tumorigenic processes by
modulation of estrogen activity. We have addressed this question
by examining the effect of dietary fiber in ovariectomized rats since
ovaries are the major source of estrogen in rats. We observed a
highly significant reduction in total mammary tumors, carcinomatous and benign, with 9.6% dietary fiber in ovariectomized rats.
Indeed, the strong suppression of mammary tumorigenesis by
dietary fiber was comparable quantitatively in the intact and
ovariectomized carcinogen-treated rats. Mammary tumors that
arise in ovariectomized animals are ovarian hormone-independent
for growth processes. That dietary fiber can suppress the developmental growth of such tumors suggests that mechanisms other than
modulation of estrogen activities also must be considered to
explain the beneficial effect of fiber. Our demonstration that uterine
weight in the ovariectomized rats was not affected by the dietary
fiber provides evidence that the fiber used in these studies does not
contain or generate agonistic or antagonistic estrogenic activities.
443
A mechanism that warrants increased attention is that dietary
fiber consumption results in a considerable increase in fecal bulk
and weight, as observed in our studies; decreased fecal transit time
also is associated with dietary fiber consumption. The above factors
may result in an increased excretion of high calorie-generating
dietary components as well as an enhanced elimination of dietary
and bowel components from microbial activities that might have
tumor growth-promoting activities. Reports suggest that dietary
fiber may have immunoregulatory effects on the intestinal immune
system (Tappenden et al., 1995; Lim et al., 1997) and, thus, may
enhance systemic immune defenses. In all of these experiments, the
feeding of dietary fiber did not cause any apparent adverse health effects
or any significant changes in body weight gains of the animals.
Our salient conclusions are that dietary fiber at the 9.6% level is
very effective in suppressing the development of mammary gland
tumors in an impressive array of animal models for this disease,
i.e., in carcinogen-treated intact rats (develops primarily ovarian
hormone-dependent mammary tumors), in carcinogen-treated ovariectomized rats (develops ovarian hormone-independent mammary
tumors, carcinomatous and benign), in rodents that develop mammary tumors spontaneously (C3H/HeOuJ mice, MTV-enhanced)
and in a transplantable mammary tumor model (C3H/HeOuJ
mice/ATCC-CRL-1637 cells). It is hoped that our results will
encourage continued study of the relationship between dietary fiber
and tumorigenic processes and facilitate a mechanistic understanding of this relationship.
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