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2
Departments of
*
Nutritional Sciences and
Animal Sciences, Rutgers, the State University of New Jersey, New Brunswick, New Jersey 08901
2To whom correspondence should be addressed at Rutgers, The State University of New Jersey, Department of Animal Sciences, 59 Dudley Road, 108 Foran Hall, New Brunswick, NJ 08901-8502. E-mail: cohick{at}aesop.rutgers.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • iron deficiency • mammary gland • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,2)
. The terminal end bud
(TEB),3
the least
differentiated of the glandular structures, has been shown to be the
site of cancer initiation in rat models of carcinogenesis
(2
,3)
. Therefore, factors that modify the developmental
profile of the gland may also modify breast cancer risk.
Postnatal mammary gland development is largely controlled by steroid
and peptide hormones, as well as by peptide growth factors. In
addition, dietary constituents influence glandular development in the
rat. Maternal diets low in protein (4)
or high in fat
(5
,6)
increase the number of TEB and decrease the number
of alveolobules (LOB) of female offspring. In contrast, dietary
genisten, the major isoflavone found in soy, is associated with
enhanced glandular development in the rat (7)
.
An association between iron deficiency and breast cancer has not been
reported in epidemiological studies, but we find the association both
plausible and intriguing. Anemia, which often goes undetected and
untreated, is a common clinical finding that is coincident during the
breast cancer susceptibility timeframe. In addition, iron is critical
for many aspects of cellular physiology (8
9
10
11)
, and
alterations in several of these processes have been implicated in
cancer etiology (1)
. Finally, many of the classic clinical
manifestations of iron deficiency anemia involve impairments of
epithelial cell growth and development.
We have previously shown that moderate iron deficiency increases
7,12-dimethylbenz[a]anthracene (DMBA)-induced breast tumor
incidence and burden in virgin female Sprague-Dawley rats
(12)
. The carcinogenic potential of DMBA is dependent on
the developmental stage of the mammary gland. The least differentiated
TEB has been shown to be the target structure of DMBA
(13)
, and tumor incidence is directly related to the
number of TEB (5
,7
,14)
. Therefore, we hypothesized that
the induction of moderate iron deficiency in prepubertal female rats
would result in impaired alveolobular development of the gland as
characterized by an increase in the number of TEB and a decrease in the
number of LOB relative to controls. This hypothesis was tested in a rat
model of iron deficiency by examining the morphological development of
the mammary gland during moderate and severe iron deficiency.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Female weanling Sprague-Dawley rats (Harlan Sprague Dawley,
Indianapolis, IN) were randomly assigned to either control or treatment
groups (n = 5). Rats were individually housed in
wire mesh cages and maintained on a 12-h light/dark cycle. Rats were
fed a pelleted semipurified AIN-76 diet (15)
(Science
Diets, Piscataway, NJ) formulated to provide all recommended nutrients
as previously described (12)
, with the exception that iron
sulfate was added at 35 mg Fe/kg diet (control), 12 mg Fe/kg diet
(moderate) or 6 mg Fe/kg diet (severe). Rats were allowed free access
to diets and distilled deionized water. Food intake was recorded daily,
and rats were weighed each week. Estrous phase was determined by
microscopic examination of vaginal smears. Rats were fed the
experimental diets for 6 wk and killed at 63–65 d of age while in
estrus. At 2 h before killing, rats received an intraperitoneal
injection of 5-bromo-2'-deoxyuridine (BrdU) (100 mg/kg body; Sigma
Chemical Co., St. Louis, MO) dissolved in dimethylsulfoxide. Rats were
exposed to ether, and closed cardiac puncture was performed. Cardiac
blood was used to measure hematocrit and hemoglobin at the time of
killing. Plasma was collected from the remaining blood sample and
stored at -80°C for hormone analyses. Livers were excised, weighed,
frozen in liquid nitrogen and stored at -80°C. Liver iron levels
were measured on a flame atomic absorption spectrophotometer (Thermo
Jarrell Ash, Franklin, MA) after dry ashing at 500°C and digestion in
concentrated nitric acid. All conditions and handling of rats met
National Institutes of Health guidelines for the care and use of
laboratory animals (16)
.
Mammary tissue.
Mammary tissue was obtained from rats by removing the intact pelt containing all six pairs of mammary glands. The pelt was stretched and fixed in 10% neutral buffered formalin (Fisher Scientific, Pittsburgh, PA) for 48 h. The left third thoracic and fourth abdominal mammary glands were excised and processed for whole mounting. The entire fat pad containing the intact mammary gland was dissected from the pelt, defatted in acetone for 24–48 h, hydrated through a graded series of ethanol to distilled water, stained with toluidine blue, dehydrated through a graded series of ethanol and cleared in xylene. Stained glands were microdissected to achieve maximum resolution of the gland and mounted on glass slides using Permount (Fisher Scientific, Pittsburgh, PA).
The contralateral glands were removed from the pelt and processed for paraffin embedding. Briefly, tissues were dehydrated through a graded series of ethanol to xylene, embedded in paraffin blocks, sectioned at 5 µm and mounted on Superfrost slides (Fisher Scientific) for detection of BrdU incorporation by immunohistochemistry.
Mammary gland morphological analysis
The effect of iron deficiency on mammary gland development was
determined by microscopic examination of toluidine blue–stained
mammary gland whole mounts. The classification and quantification of
the different mammary gland structures were performed using a
stereomicroscope fitted with an ocular micrometer. The microscope was
calibrated using a 1-mm stage micrometer. The type and number of
mammary gland structures were determined within a defined area that
encompassed the periphery of the gland. Structures were classified as
TEB, terminal ducts or LOB based on the criteria developed by Russo and
Russo (13)
. TEB, which are the growth point of the mammary
epithelial tree, are abundant at the periphery of the gland, so this
area was chosen for study. TEB are identified by their club-shaped
morphology and exist as solitary structures or in clusters. In whole
mount preparations, classification is confirmed by a minimum diameter
of 100 µm when measured at the widest point. In longitudinal
sections, TEB appear round or oval shaped with multiple layers of
epithelial cells enclosing a central duct. The terminal duct, which
represents a TEB in the process of regression (13)
,
appears as slender TEB in whole mount preparations. Classification is
confirmed by a diameter of <100 µm. In longitudinal sections,
terminal ducts appear as ducts with a single layer of epithelial cells
and a central lumen. Alveoli consist of two to five alveolar buds
clustered around a central duct. In the present study, TEB undergoing
the process of cleavage were classified as alveoli. Lobules arise from
the further cleavage of alveolar structures to form clusters of six or
more alveolar buds. For this study, these two related structures were
grouped under the single classification of LOB. In longitudinal
sections, LOB structures are identified as clusters of acini composed
of a single layer of myoepithelial cells and a single layer of
epithelial cells enclosing a central lumen.
The densities of the different mammary structures within the third and fourth glands were determined by first dividing the gland into grids of 0.5 x 0.5 cm. Structures within each grid were then classified and quantified. The data were expressed as the number of each structure present within 1 cm2 of gland. Coded whole mounts from each treatment group were counted in duplicate with a minimum of 1 wk between determinations (r2 = 0.812).
Puberty onset and reproductive hormone levels.
Sexual maturation was established by monitoring the day of vaginal opening. Plasma levels of 17-ß-estradiol and progesterone at the time of killing were determined using standard radioimmunoassay kits according to the manufacturer’s directions (Coat-A-Count; Diagnostic Products Corp., Los Angeles, CA).
DNA-labeling index.
The effect of iron deficiency on mammary epithelial cell (MEC) DNA synthesis was determined in rats fed 12 and 35 mg Fe/kg diet. Mammary tissue sections of 5 µm thickness were heat immobilized overnight at 60°C, deparaffinized in xylene and rehydrated through a graded series of ethanol to distilled water. Endogenous peroxidase activity was quenched by a 30-min incubation in 3% H2O2. Antigen unmasking was accomplished by incubation in 2 mol HCl/L at 40°C for 1 h. Nonspecific binding of IgG was blocked by incubation in 5% horse serum (Vector Labs, Burlingame, CA). Anti-BrdU antibody (Amersham, Piscataway, NJ) was diluted 1:100 in Tris-buffered saline (TBS). After an overnight incubation at 4°C in a humidified chamber, slides were incubated with horse anti-mouse biotinylated secondary antibody (Vector Labs) followed by treatment with horseradish peroxidase–conjugated streptavidin (Vector Labs). 3,3'-Diaminobenzidine tetrahydrochloride (Vector Labs) was used as the chromogen. Slides were lightly counterstained with hematoxylin. Sections incubated with nonimmune serum were used as negative controls. Immunostaining was evaluated using a bright field microscope. The number of nuclei staining brown was expressed as a percentage of the total number of nuclei counted.
Statistical analysis.
Data were analyzed by one-way ANOVA and Fisher’s protected least significant difference test using StatView software for Macintosh. Differences were considered significant when P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Iron-restricted diets providing 6 or 12 mg Fe/kg diet resulted in
the development of severe or moderate iron deficiency, respectively, as
determined by hematological indices and body iron stores (Table 1
). Hematocrit and hemoglobin were significantly lower (32 and 45%,
respectively) in rats fed 6 mg Fe/kg diet than in controls
(P < 0.05). Rats fed 12 mg Fe/kg diet tended to have
lower hematocrit and hemoglobin values compared to controls (16% and
13%, respectively), but these differences were not significant
(P = .12). In contrast, liver iron stores were significantly
depleted in moderately as well as severely deficient rats compared with
controls (P < 0.05). Final body weights did not differ
among groups (data not shown).
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Mammary gland development and DMBA-induced carcinogenesis are
hormone-dependent processes. In addition, mitotic activity of the
MEC varies with phase of the estrous cycle, increasing during the
luteal phase and decreasing in the follicular phase
(13
,17)
. Therefore, in addition to measuring estrogen and
progesterone levels, puberty onset was also established. Feeding 6 or
12 mg Fe/kg diet beginning at 21 d of age did not affect the onset
of sexual maturity; control and treated rats reached sexual maturity at
35 d. Plasma estrogen levels did not differ among groups
(P = 0.54), but plasma progesterone levels were
significantly lower in both iron-restricted groups than in controls
(P < 0.05, Table 1
).
Mammary gland morphogenesis.
The effect of iron deficiency on mammary gland morphogenesis was
evaluated in both thoracic and abdominal mammary glands after 6 wk of
iron restriction. The overall size and gross morphology of the
abdominal glands were similar in iron-deficient and control rats
(Fig. 1
). Similar results were obtained for the thoracic glands (data not
shown). Because the leading edge of the gland is the area richest in
TEB, this region was chosen for study. The area (in
cm2) of thoracic (P = 0.82) and
abdominal (P = 0.57) glands included for
study did not differ among groups. TEB and LOB were present in the
glands of all rats regardless of dietary treatment. The density of
thoracic TEB in severely and moderately iron-deficient rats did not
differ from controls (P = 0.20) (Table 2
). The degree of iron deficiency also had no effect on the density of
TEB in the fourth abdominal gland (P = 0.16).
Similarly, LOB development in thoracic (P = 0.82) and
abdominal glands (P = 0.57) was unaffected by dietary
iron.
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We have found that only moderate, and not severe, iron deficiency
leads to increased tumor incidence and burden in response to chemical
carcinogen exposure. This is the condition that most closely reflects
the average premenopausal woman living in industrialized societies.
Therefore, the DNA-labeling index was studied in only the
moderately iron-deficient and control groups. In addition, only the
thoracic gland was studied because we have found that this site
accounts for the majority of between-group differences in mammary
gland tumor burden (number of tumors per rat). BrdU incorporation was
used to determine the percentage of epithelial cells in S-phase of
the cell cycle at the time of killing. Within the treatment and control
groups, the DNA-labeling index was highest in the TEB and lowest in
the LOB (Fig. 2
). This is in agreement with the results of others (18)
.
DNA synthesis in the TEB of iron-deficient rats did not differ from
controls (P = 0.29). We found no effect of
moderate iron deficiency on MEC proliferative activity in any of the
other ductal structures studied.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Although DMBA does not
exist in the natural environment, it is widely used as a model for the
class of environmental carcinogens known as polycyclic aromatic
hydrocarbons. Therefore, we found these results to represent
potentially important health consequences for women. This fact becomes
especially salient when the many similarities in mammary gland
development between humans and rats are considered
(18)
. Despite the exquisite mechanisms of iron homeostasis
that have evolved among eukaryotes and the fact that iron is the second
most abundant metal on earth, iron deficiency remains the most common
nutritional deficiency worldwide. Recent estimates from the World
Health Organization indicate that among premenopausal women, 20–30%
in developing and 5–10% in developed countries are iron deficient
(19)
. In the United States, iron deficiency anemia among
children, adolescents and premenopausal women is still fairly common,
despite iron fortification of the food supply. Results from the
National Health and Nutrition Education Survey III indicate that 7.8
million women of reproductive age are iron deficient in the United
States, of whom 4.5 million are iron deficient without anemia
(20)
. In addition, it has been suggested that adolescent
girls in developing and industrialized nations consume inadequate
dietary iron (21)
. Together, these figures portend an
important potential health risk.
Many factors have been shown to influence the carcinogenic potential of
DMBA, including age, reproductive hormone levels and the rate of target
cell proliferation (14
,22)
. The goal of the present study
was to identify potential mechanisms mediating the increase in tumor
outcome observed during moderate iron deficiency in rats
(12)
. We investigated the effect of iron restriction on
mammary gland development, MEC proliferation and ovarian function.
Feeding iron-restricted diets that provide 6 and 12 mg Fe/kg diet
to female weanling rats resulted in the development of severe and
moderate iron deficiency as indicated by hematological indices and
liver iron concentration. Moderate iron deficiency was characterized by
a significant depletion of body iron stores, which was reflected in the
decreased liver iron content. In contrast, the hematocrit and
hemoglobin levels, although decreased, were not significantly different
from those of control rats. Clinically, iron deficiency anemia is
defined as hemoglobin values that are 2 SD below the
population mean (23)
. However, the determination of
moderate iron deficiency, or iron deficiency without anemia, is more
ambiguous. In the National Health and Nutrition Education Survey III
study, the designation of iron deficiency without anemia was based on
an individual having a normal hemoglobin with two or more other
indicators of iron status that fell below a predetermined cutoff value
(20)
. In our studies, moderate iron deficiency was defined
as having nonsignificant reductions in hemoglobin and hematocrit but a
significant reduction in body iron stores. These criteria are
consistent with the clinical picture of moderate iron deficiency seen
in premenopausal women in the United States, a condition that was our
intention to mimic.
Normal postnatal mammary gland development is dependent in part on the
action of the reproductive hormones (24)
. In addition, the
mitotic activity of the MEC in humans and rats is influenced by
the phase of estrus (13
,17)
. Therefore, it was important
to establish the effect of dietary treatment on these variables. Iron
status had no effect on the onset of sexual maturity. Circulating
levels of 17-ß-estradiol were not affected by either severe or
moderate iron deficiency. In contrast, iron restriction was associated
with a significant reduction in plasma progesterone levels relative to
control rats. Our results indicate that the lower progesterone levels
did not affect mammary gland growth or development. Therefore, the
physiological relevance of this finding is unclear at the present time.
Progesterone has been shown to regulate, either directly or indirectly,
the iron-containing proteins lactoferrin (25
,26)
and
uteroferrin (27)
. Whether these two findings are related
remains to be determined. In contrast, the effect of iron deficiency on
circulating progesterone levels has not been reported. One possibility
would be that the metabolism of progesterone is altered in iron
deficiency. Clearly, this observation warrants further investigation.
In rats, pubertal development of the mammary gland is
characterized by a rapid expansion of the mammary parenchyma largely
through the mitotic activity of the TEB. It has been estimated that
mammary gland growth proceeds at a rate four times that of body growth
between 23 to 40 d of age in rats (28)
. The
ubiquitous role of iron in cellular physiology would be expected to
place a large demand on iron stores during this increase in cellular
growth. We found no significant effects of iron status on postpubertal
mammary gland morphology when iron deficiency was initiated at 21 d of age in the female rat. Although the density of TEB in the thoracic
gland was numerically higher in both iron-restricted groups
compared with control rats, the differences were not statistically
significant. Thoracic mammary gland development was studied in three to
five rats per group. Therefore, the lack of significant treatment
effects may be due to the combination of subtle changes in gland
development and the small sample size studied. It is possible that
evaluation of a greater number of glands would have reduced the
within-group variability, resulting in significant differences
among groups.
Results in BrdU labeling confirm the morphological findings. The
incorporation of BrdU was similar between moderately deficient and
control rats in all structures examined. In contrast to the present
observations in the mammary epithelium, thymic and splenic atrophy has
been observed in rats with similar degrees of iron deficiency
as achieved in the present study (29
,30)
. The apparent
differences in the proliferative or growth capabilities of these two
cell types during similar conditions of iron depletion raise
interesting questions regarding the prioritization of iron utilization
among different tissues during the depletion of body iron stores.
Little information is available concerning the regulation of iron
homeostasis in the MEC. However, because cellular iron homeostasis is
regulated at the level of iron uptake, one mechanism governing such a
prioritization is the regulation of transferrin receptor (TfR)
expression (31)
. TfR expression has been shown to be
increased in proliferating MEC and T-lymphocytes
(32
33
34)
. However, in contrast to the present results,
which indicate no effect of iron deficiency on MEC proliferation, iron
deficiency does significantly impair T-lymphocyte proliferation.
This suggests that factors other than TfR expression may be mediating
iron uptake and utilization in the mammary gland during iron
restriction.
We had hypothesized that iron deficiency would impair the morphological development of the mammary gland and that this would be manifested as an increase in the numbers of precursor structures, the TEB. An increase in TEB density could then account for our observation that moderate iron deficiency is a risk factor for DMBA-induced tumor formation in the rat. The data presented here do not support this hypothesis. The possibility that moderate iron deficiency may lead to subtle metabolic abnormalities at the cellular level or impair defense mechanisms directed toward elimination of genetic damage warrants further examination.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BrdU, 5-bromo-2'-deoxyuridine; DMBA, 7,12-dimethylbenz[a]anthracene; LOB, alveolobule; MEC, mammary epithelial cell; TEB, terminal end bud; TfR, transferrin receptor.
Manuscript received November 30, 2000. Initial review completed January 3, 2001. Revision accepted February 24, 2001.
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REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Adami H. O., Signorello L. B., Trichopoulos D. Towards an understanding of breast cancer etiology. Semin. Cancer Biol. 1998;8:255-262[Medline]
2. Russo J., Russo I. H. Cellular basis of breast cancer susceptibility. Oncol. Res. 1999;11:169-178[Medline]
3. Russo J., Russo I. H. DNA labeling index and structure of the rat mammary gland as determinants of its susceptibility to carcinogenesis. J. Natl. Cancer Inst. 1978;61:1451-1459
4. Alvarez Sanz M. C., Liu J. M., Huang H. H., Hawrylewicz E. J. Effect of dietary protein on morphologic development of rat mammary gland. J. Natl. Cancer Inst. 1986;77:477-487
5.
Hilakivi-Clarke L., Clarke R., Onojafe I., Raygada M., Cho E., Lippman M. A maternal diet high in n-6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Proc. Natl. Acad. Sci. U.S.A. 1997;94:9372-9377
6.
Hilakivi-Clarke L., Stoica A., Raygada M., Martin M. B. Consumption of a high-fat diet alters estrogen receptor content, protein kinase C activity, and mammary gland morphology in virgin and pregnant mice and female offspring. Cancer Res 1998;58:654-660
7.
Fritz W. A., Coward L., Wang J., Lamartiniere C. A. Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. Carcinogenesis 1998;19:2151-2158
8.
Reichard P., Ehrenberg A. Ribonucleotide reductase–a radical enzyme. Science 1983;221:514-519
9.
Cooper C. E., Lynagh G. R., Hoyes K. P., Hider R. C., Cammack R., Porter J. B. The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase. J. Biol. Chem. 1996;271:20291-20299
10.
Cryns V., Yuan J. Proteases to die for. Genes Dev 1999;13:371-390
11.
Gross A., Yin X. M., Wang K., Wei M. C., Jockel J., Milliman C., Erdjument-Bromage H., Tempst P., Korsmeyer S. J. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J. Biol. Chem. 1999;274:1156-1163
12. Spear A. T., Sherman A. R. Iron deficiency alters DMBA-induced tumor burden and natural killer cell cytotoxicity in rats. J. Nutr. 1992;122:46-55
13. Russo J., Russo I. H. Biological and molecular bases of mammary carcinogenesis. Lab. Invest. 1987;57:112-137[Medline]
14.
Tay L. K., Russo J. Formation and removal of 7,12-dimethylbenz[a]anthracene–nucleic acid adducts in rat mammary epithelial cells with different susceptibility to carcinogenesis. Carcinogenesis 1981;2:1327-1333
15. American Institute of Nutrition Report of the American Institute of Nutrition Ad-Hoc Committee on Standards for Nutritional Studies. J. Nutr. 1987;107:1340-1348
16. National Research Council Guide for the Care and Use of Laboratory Animals 1985 National Institutes of Health Bethesda, MD.
17. Potten C. S., Watson R. J., Williams G. T., Tickle S., Roberts S. A., Harris M., Howell A. The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br. J. Cancer. 1988;58:163-170[Medline]
18. Russo J., Gusterson B. A., Rogers A. E., Russo I. H., Wellings S. R., van Zwieten M. J. Comparative study of human and rat mammary tumorigenesis. Lab. Invest. 1990;62:244-278[Medline]
19. Yip R. Iron deficiency. Bull. World Health Organ. 1998;76:121-123
20.
Looker A. C., Dallman P. R., Carroll M. D., Gunter E. W., Johnson C. L. Prevalence of iron deficiency in the United States. J. Am. Med. Assoc. 1997;277:973-976
21. Beard J. L. Iron requirements in adolescent females. J. Nutr. 2000;130:440S-442S
22.
Welsch C. W. Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins. Cancer Res 1985;45:3415-3443
23. Cook J. D. Iron-deficiency anaemia. Baillieres Clin. Haematol. 1994;7:787-804[Medline]
24. Medina D. The mammary gland: unique organ for the study of development and tumorigenesis. J. Mam. Gland Biol. Neoplasia 1996;1:5-19
25.
McMaster M. T., Teng C. T., Dey S. K., Andrews G. K. Lactoferrin in the mouse uterus: analysis of the preimplantation period and regulation by ovarian steroids. Mol. Endocrinol. 1992;6:101-111
26.
Kurita T., Lee K. J., Cooke P. S., Lydon J. P., Cunha G. R. Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus. Biol. Reprod. 2000;62:831-838
27.
Fliss A. E., Michel F. J., Chen C. L., Hofig A., Bazer F. W., Chou J. Y., Simmen R. C. Regulation of the uteroferrin gene promoter in endometrial cells: interactions among estrogen, progesterone, and prolactin. Endocrinology 1991;129:697-704
28.
Sinha Y. N., Tucker H. A. Mammary gland growth of rats between 10 and 100 days of age. Am. J. Physiol. 1966;210:601-605
29. Kochanowski B. A., Sherman A. R. Cellular growth in iron-deficient rat pups. Growth 1982;46:126-134[Medline]
30.
Helyar L., Sherman A. R. Iron deficiency and interleukin 1 production by rat leukocytes. Am. J. Clin. Nutr. 1987;46:346-352
31.
Huebers H. A., Finch C. A. The physiology of transferrin and transferrin receptors. Physiol. Rev. 1987;67:520-582
32. Schulman H. M., Ponka P., Wilczynska A., Gauthier Y., Shyamala G. Transferrin receptor and ferritin levels during murine mammary gland development. Biochim. Biophys. Acta 1989;1010:1-6[Medline]
33. Seligman P. A., Kovar J., Gelfand E. W. Lymphocyte proliferation is controlled by both iron availability and regulation of iron uptake pathways. Pathobiology 1992;60:19-26[Medline]
34.
de Silva D. M., Askwith C. C., Kaplan J. Molecular mechanisms of iron uptake in eukaryotes. Physiol. Rev. 1996;76:31-47
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