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3 Department of Medicine, Division of Medical Oncology and Colorado Cancer Center, University of Colorado Health Science Center, Aurora, CO 80010; 4 AMC Cancer Research Center, Denver, CO 80214; 5 Department of Veterinary Physiology and Pharmacology, Texas A & M, College Station, TX 7784; 6 Department of Human Nutrition, University of Illinois at Chicago, Chicago, IL 60612; 7 Consultant, 8 Department of Preventive Medicine, University of Colorado Health Science Center, Aurora, CO 80010; 9 Cancer Prevention Laboratory, Colorado State University, Fort Collins, CO 80523; and 10 Department of Obstetrics and Gynecology, Division of Basic Science, University of Colorado, Aurora, CO 80010
* To whom correspondence should be addressed. E-mail: pepper.schedin{at}uchsc.edu.
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0.7, P 
0.002), which was associated with a reduction in alveolar gland development. The S diet suppressed the onset of sexual maturation (P < 0.001) and inhibited markers of mammary alveologenesis more than the RP diet. These data demonstrate that the amount and source of vitamin A consumed by adolescent female rats can influence the onset of puberty, mammary gland alveolar development, and breast cancer risk and highlight the relevance of utilizing whole-food diets to evaluate the role of dietary factors in cancer prevention.
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Introduction |
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25% of all breast cancer cases (1–3). Data from twin studies support the conclusion that nutritional and lifestyle factors dominate over genetic predisposition in cases of sporadic breast cancer (4). Although the link between diet and breast cancer is clearly established, the dietary components responsible for protection and their mechanisms of action remain largely unknown. The current paradigm for animal nutrition studies is to investigate a single dietary component in the context of a defined diet. Although useful, this model does not reproduce the complex phytochemical interactions that may underlie the protective effects of diet on carcinogenesis. Specifically, the biological activity of a single nutrient can be altered by the presence of other dietary components. Furthermore, the approach of investigating a single nutrient does not consider the fact that there are multiple biologically active compounds present in foods that may contribute to their overall beneficial effects. It has been suggested that the progress toward elucidating the role of diet in cancer will require a more holistic approach (5–7). To this end, we developed a human-food–based rodent diet, composed of foods purchased from grocery stores, to investigate the effects of vitamin A on adolescent rat mammary gland development and the subsequent risk for mammary carcinogenesis. Our focus on the role of vitamin A intake and breast cancer risk is based on epidemiological and clinical reports that have correlated elevated vitamin A intake with a modest reduction in breast cancer and on numerous confirmatory experiments using preclinical rodent models (3,8–16). We propose that vitamin A–based dietary interventions targeted to adolescent populations may provide even greater protection than the same intervention in adults (17). This argument is based on observations identifying the years between the onset of puberty and first childbirth as a "hot spot" for establishing breast cancer risk (18–21). Specifically, during puberty, the actively developing mammary gland is anticipated to be influenced by nutrient intake in a manner analogous to the influence of maternal diet on embryonic development (17,18). Thus, it is predicted that dietary intervention during adolescence may impact mammary gland development and the subsequent susceptibility of the mature gland to cancer (17,18,22), which is substantiated by reports that childhood soy consumption is associated with a greater reduction in breast cancer risk than adult soy consumption (23,24).
To test a dietary prevention strategy using physiologically relevant levels of vitamin A, we restricted our rodent studies to levels of vitamin A that can be obtained from a nutritionally balanced diet. To examine the impact of diet during adolescence, we modeled human adolescent development by targeting dietary intervention to young female rats from 21 to 63 d of age [postnatal day (p)1121–p63]. This 42-d window of rodent development, characterized by rapid body growth, sexual maturation, and mammary gland development, correlates with puberty in humans (25). Using this model, we evaluated whether moderate vitamin A supplementation, via a whole-food diet or as a chemical additive, altered mammary gland development and mammary cancer in female rats.
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18.5% energy from protein, 60% from carbohydrate, and 22% from fat (Table 2). Macronutrient and micronutrient contents of the whole-food diets were estimated using the University of Minnesota's Nutrition Data System for Research, version 4.02/30 (27).
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10% (data not shown). Thus, we reduced the amount of RP added to the deficient diet by 10%. The study diets were referred to as adequate (Ad), ß-carotene-rich fruits and vegetable Supra A (S), and RP-supplemented (RP). With the exception of vitamin A levels and the source of vitamin A, the macronutrient and micronutrient composition of the Ad, S, and RP diets were matched (Table 2). The only important difference between the S and RP diets, other than the source of vitamin A, was the amount of vitamin C. The S diet had 1.5-fold more vitamin C than the RP diet (Table 2). Diets were prepared biweekly in small batches from cooked foods, except for fruits and vegetables, which were added raw. Diets were homogenized and stored at –20°C. The variation in vitamin A between batches was <5%, which was confirmed by HPLC. Using HPLC, we verified that the vitamin A concentrations of the diets remained stable over the course of a typical feeding period (data not shown).
Adolescent development study. To assess dietary effects on adolescent mammary gland development, p20 female Sprague-Dawley rats (Taconic Farms) were randomized into 1 of 3 dietary groups (6 rats per group) and housed 3 per cage in a controlled environment maintained at 22°C, 50% relative humidity, and a 12:12-h light to dark cycle. Rats were fed experimental diets from p21 to p63 and had free access to food and distilled water. As a marker for the onset of sexual maturation, starting at p27, rats were checked daily for the appearance of the vaginal opening. To evaluate effects of diet on early estrous cycles, defined as cycles within the first 2 wk of sexual maturation, 12 rats per group received vaginal lavages daily from p43 through p50. To evaluate estrous cycles in more mature rats, 24 rats per dietary group were evaluated from p51 to p58, as previously described (28). All rats were killed by CO2 asphyxiation followed by cervical dislocation at p63. Left mammary gland chains 4–6 were harvested for whole-mount histological analyses. Right mammary gland chains 4–6 were harvested, and the lymph node in gland 5, with adjacent mammary tissue, was processed for histology. The remaining lymph-free mammary tissue was quickly frozen in liquid nitrogen and stored at –80°C for biochemical assays. The stage of the rat's estrous cycle at time of killing was determined by vaginal smear cytology, and by histological analyses of cervical tissue taken at time of killing (28).
Morphological characterization of mammary gland. Whole-mount preparations of mammary gland chains 4–6 were prepared and photographed as previously described (28). Tertiary branching was quantified from whole-mount images by measuring the length of secondary ducts and the number of tertiary side branches. Alveolar development was quantified by counting the number of acini per lobule according to methods originally described by Russo et al. (29). Total glandular (epithelial) content of gland 5 was quantified by converting digital whole-mount images to grayscale using Adobe Photoshop 7.0. The total number of pixels and the percentage of pixels representing epithelium were obtained using previously described methods (30). Values are percentages of epithelium per field ± SEM.
Ki-67 proliferation analysis. To control for differences in proliferation indices that may be due to regional variation within the mammary gland, only mammary tissue samples adjacent to the lymph node chain in gland 5 were evaluated. Immunohistochemical detection of Ki-67 positive cells was performed using rabbit anti-Ki-67 (Lab Vision, RM-9106) according to the manufacturer's instruction. Sections were counterstained with Harris Hematoxylin. Between 8 and 12 random fields per gland were photographed at 400x. Ki-67 positive epithelial cells and total number of epithelial cells were counted by 2 independent investigators who were unaware of treatment protocol. At p63 (the age of the rats utilized for the Ki67 analysis), there were few terminal end bud structures (TEB) present, and epithelial cells associated with TEB were not included in the proliferation analysis. A mean of 1321 mammary epithelial cells (range 669–2708) were counted per mammary gland per rat. The percentage of Ki-67 positive cells was expressed as means ± SEM.
Isolation of RNA and RNase protection analyses.
Total mammary gland RNA was isolated from individual rats (mammary gland chains 4–6 with lymph nodes removed) using RNAwiz (Ambion) and RNA from 6 rats/group was pooled. Rats in the RP group were segregated into 2 groups based on morphology; those with alveolar development (n = 3) and those without (n = 3). RNase protection assays were performed using RPA III kits (Ambion) according to the manufacturer's supplied protocol. A whey acidic protein (WAP) probe was generated by RT-PCR cloning of DNA fragments amplified from rat mammary gland RNA into pGEM-T Easy (Promega). Primers used to generate the WAP probe corresponded to bases 160–385 of the reported sequence (25); and probes for c-Myc correspond to the published sequence (31). The sequence of probe-containing plasmids were verified (University of Colorado Health Sciences Center DNA Sequencing Core Facility) and linearized by restriction enzyme digestion prior to T7 RNA polymerase-mediated probe generation in the presence of [
-32P] UTP using Maxiscript kits (Ambion). The rat ß-actin probe, pTRI-ß-actin-125-rat, was purchased from Ambion.
Tissue and diet fat-soluble vitamins and carotenoids.
Experimental diets, mammary glands, and liver samples were analyzed for vitamin A and carotenoid content according to previously published HPLC procedures (32). A Waters 490 programmable multi-wavelength detector was used to detect retinol at 325 nm, and carotenoids at 450 nm. Data were processed using the Millennium computer program and custom-made software. This method separates provitamin A carotenoids (ß-carotene, -carotene, ß-cryptoxanthin) and other common carotenoids in human diet (lycopene, lutein). To calculate vitamin A content of diets, retinol and provitamin A carotenoids were converted to IU, as retinol activity equivalents are not directly applicable to rats. Conversion to IU was based on factors recommended by the Food and Nutrition Board of the Institute of Medicine (33).
Plasma retinol and carotenoids. Plasma samples were obtained from CO2-asphyxiated rats by orbital eye bleed at time of kill. Blood was collected under low light into lithium heparin-coated tubes. Samples were centrifuged at 1200 x g for 10 min at 4°C, the plasma removed, and stored, protected from light, at –80°C until HPLC analysis and according to a previously published method (34). Aliquots of thawed plasma (0.2 mL) were deproteinized, retinyl acetate was added as an internal standard, and samples were evaporated under a vacuum. Reconstituted samples were analyzed by HPLC.
Plasma progesterone and estradiol. Rat plasma was collected at p63 and stored at –80°C until analysis. Circulating estradiol and progesterone hormone concentrations were assayed using the Cayman Chemical Progesterone EIA kit (582601) and Estradiol EIA kit (582251) according to the manufacturer's protocols, and results were compared with a standard curve.
Carcinogenesis study. One hundred thirty five p20 rats were randomized into the 3 dietary groups of 45 rats per group and fed experimental diets, described above, from p21 to p63. All rats received a vitamin A–adequate diet [AIN-93M, Harlan Teklad (26)] from 64 d of age until study termination, thus limiting the dietary intervention to the period of adolescent mammary gland development. At p66, rats received a single i.p. injection of 50 mg/kg body wt of 1-methyl-1-nitrosourea (MNU). Rats were palpated twice per week for 6 mo for the detection of mammary tumors. At the end of the study, rats were asphyxiated with CO2, killed by cervical dislocation, and tumors excised, weighed, and processed for histological evaluation. Mammary tumors were classified histologically using the criteria of Young and Hallowes (35), and only adenocarcinomas were included in the subsequent analyses. MNU was provided by the National Cancer Institute's Chemical Carcinogen Reference Standards Repository operated under contract by Midwest Research Institute, MO. N02-CB-07008. The care and use of rats was in accordance with NIH guidelines and AMC Cancer Research Center Animal Care and Use Committee regulations.
Statistical analyses.
The usual distribution assumed for count data are the Poisson; group differences for tumor multiplicity were evaluated by Poisson regression (36). For statistical analyses of sexual maturation data, the number of rats with vaginal openings was modeled as a repeated measures Poisson regression, with group specified as a cluster because daily counts within a group are not independent (37); age (d) enters the model as a third-degree polynomial. Differences between groups in the final cancer incidence were evaluated by a chi-square test for independent proportions (38). The effects of dietary source and amount of vitamin A on plasma levels, the percentage of gland filled with epithelium, and the number of acini per lobule were evaluated by t tests using Satterthwaite's approximation to degrees of freedom for independent samples with unequal variances (39). Differences were considered significant at P 0.05 but were not adjusted for multiple comparisons and should be interpreted with caution. Values are means ± SEM, unless otherwise noted.
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80 IU vitamin A per kg diet or 1.8% of the human RDA. The Ad diet, designed to have 3245 IU equivalents of vitamin A per kg diet, was found to have 4300 IU/kg diet. The S and RP diets, designed to have 7-fold increase in vitamin A over the Ad diet levels, were found to have 5.5- and 6.2-fold increases with 23,570 and 26,790 IU/kg diet, respectively. Importantly, the S and RP diets had similar amounts of vitamin A per unit of energy, at 3.32 IU/kJ and 3.39 IU/kJ, respectively. Body weights. Rats were fed the Ad, S, or RP diets from p21 to p63, the window of sexual maturation in the Sprague Dawley rats. Body weight gain (g/wk) and final body weight did not differ among the groups. Body weights at p63 were 211.1 ± 2.4 g, 206.7 ± 3.0 g, and 215.2 ± 2.1 g for A, S, and RP groups, respectively. Further, body weight gain was the same as that in adolescent female rats fed the defined rodent diet AIN-93G (25), demonstrating a compensation for lower energy density of the whole-food diets by increased food intake (data not shown).
Plasma and tissue retinol and carotenoid concentrations.
In rats fed the Ad diet, circulating plasma retinol levels were 1.6 µmol/L (450 µg/L). Circulating retinol levels did not differ among groups, which is consistent with homeostatic regulation of circulating retinol levels (Fig. 1). In contrast, stored retinol levels in the liver were elevated in rats consuming the S and RP diets (Fig. 1). These levels were 0.16, 0.63, and 1.45 µmol/g (44.5, 178.4, and 412.5 µg retinol/g of liver) for Ad, S, and RP groups, respectively. As expected, carotenoids were only detected in the livers of rats fed Ad and S diets insofar as the RP diet was carotenoid-free. Liver carotenoid levels were higher in rats fed S than those fed the Ad diet, with ß-carotene levels measured at 0.013 µmol/g (6.86 µg/g tissue) in the S group and at 0.0003 µmol/g (0.16 µg/g tissue) in the Ad group (Fig. 1). Together, these data demonstrate that dietary carotenoids from fruits and vegetables were absorbed from the intestine, converted to retinol, and stored in the liver of rats consuming the S diet. The data further suggest that carotene absorption and/or conversion to retinol was 50% as efficient as that occurring with retinyl palmitate because, despite the S and RP diets having the same IU vitamin A per kJ of diet, rats consuming the S diet had 50% less stored liver retinol concentrations than rats consuming the RP diet. In rats consuming S and RP, retinol was concentrated in the mammary gland and was above the levels found in rats consuming the Ad-diet. Mammary gland retinol concentrations were 0.002, 0.003, and 0.005 µmol/g (0.577, 0.897, and 1.483 µg/g tissue) in rats fed A, S, and RP diets, respectively (Fig. 1).
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Mammary carcinogenesis. For the carcinogenesis study, dietary interventions were limited to the p21–p63 window for adolescence and preceded carcinogen exposure. Three days after termination of the experimental diets, rats were MNU treated. At 6 mo postcarcinogen injection, latency and incidence of mammary tumors did not differ among dietary groups (Fig. 5A). Tumor multiplicity, however, was reduced in rats fed either S (P = 0.0002) or RP diets (P = 0.002) during adolescence (Fig. 5B, C).
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Discussion |
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Using whole-food diets, we found that adolescent intake of a diet high in ß-carotene-rich fruits and vegetables (or supplemented with retinyl palmitate) reduced mammary tumor multiplicity in the adult rat. Although the S and RP diets had the same amount of vitamin A per unit of energy, stored tissue retinol concentrations in rats consuming the S diet were 50% of those in rats consuming the RP diet. Of interest, the 2-fold increase in body retinol stores in the RP group did not translate into an additional reduction of mammary cancer. One possible explanation for why half the stored retinol levels in the S group provided the same level of protection as in the RP group is that other dietary components in the ß-carotene-rich foods contributed to the anticancer effects of the S diet. Such fruit- and vegetable-associated dietary components could act through vitamin A or have anticancer effects independent of vitamin A. The suppression of tumor multiplicity by the both the S and RP whole-food diets contrasts with the tumor-promoting effects observed in a previous study, where adolescent rats were fed the AIN-93G diet supplemented with RP. In that study, vitamin A supplementation was associated with a significant but modest increase in tumor incidence (relative risk 1.5, P = 0.042), multiplicity (relative risk 2.0, P = 0.036), and tumor burden (P < 0.01) (25). This latter point highlights the importance of investigating nutrient–cancer interactions in the context of whole-food based diets.
In this and previous studies, we found that vitamin A supplementation suppresses rat mammary alveologenesis (25,40). The question of whether inhibition of alveologenesis contributes to the observed anticancer effect of vitamin A is uncertain. In women, long durations of estrogen and progesterone exposure, which induce alveologenesis, are associated with increased risk of breast cancer (45). Therefore, dietary components that mitigate the bioactivity of ovarian hormones are anticipated to be protective. However, short duration hormone exposure, such as that which occurs with pregnancy or short-term estrogen and progesterone treatment, can provide significant protection against chemically induced mammary cancer (29,46,47). Concurrent with hormone-induced protection is a maturation of the undifferentiated mammary terminal end buds (TEB) into differentiated alveolar buds. TEB maturation and alveolar differentiation have been proposed to protect the mammary gland from malignant transformation (29). In contrast, studies by ourselves and others indicate that mammary glands from rodents treated with chemopreventive doses of vitamin A have a glandular complexity consistent with the inhibition of alveolar differentiation (25,40,48,49). Thus, mechanisms other than the induction of alveolar differentiation appear to account for the protective activity of vitamin A. In vitro, vitamin A inhibits the proliferation of mammary epithelial and tumor cells (50–52), which is activity consistent with chemoprevention. However, we report suppression of mammary alveologenesis without the inhibition of mammary epithelial cell proliferation. These observations are consistent with previous studies demonstrating that chemopreventive levels of retinyl acetate do not block estrogen- and progesterone-induced mammary epithelial cell proliferation in vivo (40,53). Thus, in our study, the reduced cancer multiplicity observed in rats supplemented with vitamin A during sexual maturation appears to be due to a mechanism distinct from both the induction of gland maturation and inhibition of epithelial cell proliferation. Rather, our data imply that vitamin A inhibits carcinogenesis through the suppression of alveologenesis, possibly by the loss of alveolar precursor cells. The question of whether apoptosis is increased in vitamin A–supplemented glands remains to be determined.
An unexpected effect of ingesting the ß-carotene-rich fruit and vegetable diet, S, was that it affected onset of sexual maturation without significantly affecting regularity of the estrous cycle or circulating estradiol and progesterone levels. This observation may provide insight into the timing of menarche in girls. Women with early-age menarche have about twice the risk of developing breast cancer as women with a later age of menarche (19,54). Further, since 1900, the mean age of menarche in the U.S. has steadily decreased from 16 to 13 y of age (3). Results from both prospective cohort and nested-case control studies conclude that increased height and BMI accelerate the occurrence of menarche (55). Consumption of the typical Western diet, which is dense in energy, rich in refined carbohydrates, fats, and animal proteins and low in vegetables, fruit, and fiber, is thought to contribute to the decrease in the age of menarche by increasing adipose tissue (2,56). In our study, the consumption of fruits and vegetables rich in ß-carotene delayed onset of sexual maturation independent of changes in body weight, suggesting a mechanism distinct from body fat accumulation. Cumulatively, these observations suggest that the window of adolescence may be particularly sensitive to dietary carotenoid intake because the metabolic demand of the adolescent growth spurt exceeds mean intake. The adolescent rat model described here may be useful for examining the role of diet on sexual maturation and its impact on breast cancer risk.
In summary, using a rat model of breast cancer, we demonstrated the feasibility and importance of utilizing whole-food–based diets to investigate the role of diet in breast cancer prevention. Further, to our knowledge, this is the first study to model epidemiological data correlating high fruit and vegetable intake with reduced breast cancer risk and provides a platform to investigate the mechanism of this protection. The data confirm the importance of dietary context when investigating the role of a putative protective nutrient, insofar as retinyl palmitate inhibited mammary carcinogenesis in the context of a whole-food diet but not in a defined rodent diet (25). The observation that dietary intervention, limited to the time interval for sexual maturation, significantly altered pubertal gland development, demonstrates that the developing mammary gland is highly influenced by the nutrient microenvironment. Our data further indicate that the nutrient microenvironment during adolescence can imprint subsequent breast cancer risk, supporting the hypothesis that adolescent diet is a determinant of adult breast cancer risk.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Author disclosures: S. M. McDaniel, C. O'Neill, R. P. Metz, E. Tarbutton, M. Stacewicz-Sapuntzakis, J. Heimendinger, P. Wolfe, H. Thompson, and P. Schedin, no conflicts of interest.
11 Abbreviations used: Ad, adequate; MNU, 1-methyl-1-nitrosourea; p, postnatal; RP, retinyl palmitate; S, supra A; TEB, terminal end bud; WAP, whey acidic protein.
Manuscript received 4 October 2006. Initial review completed 13 October 2006. Revision accepted 27 March 2007.
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