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* Department of Animal Science and
Department of Food Science, Cornell University, Ithaca, NY 14853;
** Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263
2To whom correspondence should be addressed. E-mail: Clement.Ip{at}RoswellPark.org.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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9-desaturase was documented previously in several species, including rats and humans. Specifically, our objective was to determine the relative contribution of dietary VA and CLA to the tissue concentration of CLA and its ability to inhibit the development of mammary carcinomas. A total of 7 diets were formulated with varying levels of CLA and VA. The overall dietary treatment scheme was designed to evaluate the modulation of mammary cancer risk by 1) small increases of CLA in the presence of a low level of VA and 2) more substantial increases of VA against a background of low levels of CLA. As expected, small increases in dietary CLA at the low end of the CLA dose-response range did not reduce tumorigenesis. In contrast, there was a distinct and marked inhibitory response to VA that was dose dependent. The effect of VA was magnified in this experiment because the dose range of VA tested was much broader than that of CLA. Fatty acid analysis showed that the conversion of dietary VA to CLA resulted in a dose-dependent increase in the accumulation of CLA in the mammary fat pad, which was accompanied by a parallel decrease in tumor formation in the mammary gland. The finding confirms that the conversion of VA to CLA is as important for cancer prevention as the dietary supply of CLA. Thus, VA is also anticarcinogenic, and VA and CLA represent functional food components that are present in ruminant fat.
KEY WORDS: • conjugated linoleic acid • vaccenic acid • milk fat • mammary cancer prevention • functional food
Numerous health benefits have been identified with conjugated linoleic acid (CLA)2 isomer mixtures in biomedical studies in animal models (1,2). Beneficial health effects have included reductions in carcinogenesis and atherosclerosis. The major dietary source of CLA is foods derived from ruminants, especially dairy products; in this case, cis-9, trans-11 CLA is the predominant CLA isomer (3,4). The cis-9, trans-11 CLA isomer is an intermediate in rumen biohydrogenation of linoleic acid, and it was originally assumed this was its source in ruminants. However, recent studies have demonstrated that the major source of cis-9, trans-11 CLA in milk fat is endogenous synthesis via 9-desaturase, with trans-11 18:1 (vaccenic acid; VA) as the precursor (5–7).
We recently established that cis-9, trans-11 CLA was anticarcinogenic in a rat mammary cancer model when it was supplied in a natural form (esterified in butter fat triglyceride) as a food component (8). Interestingly, tissue concentrations of cis-9, trans-11 CLA were greater in rats fed a butter that had been naturally enriched with cis-9, trans-11 CLA compared with rats fed a comparable amount of the same chemically prepared CLA isomer, and we postulated that this difference was related to endogenous synthesis of cis-9, trans-11 CLA from VA present in the butter. In addition to the importance of endogenous synthesis in dairy cows cited above, the conversion of VA to cis-9, trans-11 CLA has also been shown in rodents (9,10), pigs (11) and humans (12–14). Banni et al. (10) demonstrated specifically that feeding rats increasing amounts of pure VA resulted in a progressive increase in the tissue concentrations of cis-9, trans-11 CLA, and this corresponded to reductions in the number of premalignant mammary lesions after exposure to a chemical carcinogen. In the present study, we examined the effects of increasing dietary levels of VA and cis-9, trans-11 CLA concentrations (present in butter fat) on chemically induced mammary carcinogenesis in rats. Our objective was to determine the relative contributions of VA and cis-9, trans-11 CLA to the tissue concentration of cis-9, trans-11 CLA and its ability to inhibit the development of mammary carcinomas.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The dietary treatments in the rodent carcinogenesis experiment were designed to differ in the concentration of VA and cis-9, trans-11 CLA provided as a natural food. To achieve this, we formulated diets for the rats with combinations of butter from two sources. The butter sources were produced by manipulating the diets of dairy cows as previously described (15) under the auspices of the Cornell University Institutional Animal Care and Use Committee. One group of cows was fed a corn-based total mixed ration to produce a control milk fat; a second group of cows was fed the same total mixed ration supplemented with 2 g/100 g sunflower oil and 1 g/100 g fish oil to produce a milk fat that was enriched with VA and cis-9, trans-11 CLA. Milk was collected and processed from these two groups of cows to manufacture butter as previously described (15). The fatty acid composition of the two sources of butter is presented in Table 1. There were minor differences in concentrations of several fatty acids between the two butter sources, but there were major differences in the concentrations of VA and CLA.
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Female Sprague-Dawley rats were purchased from Charles River Breeding Laboratories (Raleigh, NC) at 45 d of age; all subsequent procedures were approved by Roswell Park Cancer Institute Animal Care and Use Committee. Rats were fed the AIN-76 basal diet as described previously (8) for 1 wk to acclimate them to the powdered diet. All rats were injected with a single dose of methylnitrosourea (MNU: 50 mg/kg body) intraperitoneally at 52 d of age for the induction of mammary tumors. Immediately after MNU administration, a total of 210 rats were divided into 7 groups of 30 each and administered the different dietary treatments for the following 24 wk. Throughout this period, rats were palpated weekly to determine the appearance, size and location of mammary tumors. The experiment was terminated at 24 wk after MNU administration. All tumors were excised and fixed for histological examination, and only confirmed carcinomas are reported in data summaries. Randomly selected subsets of rats (n = 9) from each treatment were necropsied. The tumor-free inguinal mammary fat pad, a portion of the liver and plasma were retrieved. Tissue and plasma samples were immediately frozen in liquid nitrogen and then stored at -80°C until fatty acid analysis.
Diet formulation and feeding.
All seven diets contained a total of 10 g/100 g butter fat, which was derived from the two butter sources either alone or in combination (Table 2). Diet A represented the control group’s diet, which contained a low level of both CLA and VA. By using different proportions of the control butter and the VA/CLA-enriched butter, diets E, F and G were formulated with increasing concentrations of VA at 0.73, 1 or 1.6 g/100 g. Because the two sources of butter contained different levels of CLA, diets B, C and D were supplemented with synthetic cis-9, trans-11 CLA (Natural, Hovdebygda, Norway; 90% purity) so that the total CLA concentration in diet B matched the CLA concentration in diet E, diet C matched diet F, and diet D matched diet G. All diets contained the same amounts of casein, dextrose, mineral mix, vitamin mix, alphacel, DL-methionine and choline bitartrate as described previously (16). Food and water were consumed ad libitum. Fresh food was given every 2 d.
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The -80°C samples of liver and mammary fat pad were pulverized at liquid nitrogen temperature. Total lipids were then extracted from pulverized tissues and plasma by the procedure of Hara and Radin (17) using hexane/isopropanol. Fatty acids were methylated according to Christie (18) with modifications. For fat pad lipids, 40 mg was dissolved in 2.0 mL hexane and 40 µL methyl acetate. Methylation reagent (40 µL of 1.0 mol/L sodium methoxide in methanol) was added, the solution was thoroughly mixed and allowed to react at room temperature for 10 min. The reaction was then terminated by the addition of 60 µL of 0.26 mol/L oxalic acid in diethyl ether. Several grains of anhydrous calcium chloride were added, and the mixture was incubated at room temperature for 1 h. An aliquot of the clear hexane supernatant was removed for analysis by GC after centrifugation at 2400 x g, 4°C for 5 min. Plasma and liver samples were processed in a manner similar to that for the mammary fat pad. However, because these typically yielded far less lipid, quantities of all reagents for methylation were adjusted to compensate for the reduced yield.
FAME were analyzed by GC (Hewlett Packard GC system 6890+ with flame ionization detector, Avondale, PA) using a CP-Sil 88 capillary column (100 m x 0.25 mm i.d. with 0.2-µm film thickness; Varian, Walnut Creek, CA). A programmed temperature run was used to separate FAME. Inlet and detector temperatures were both 250°C. The oven temperature was initially 80°C, then ramped 2°C/min to 190°C and held for 20 min until ramped 5°C/min to 215°C and held for 15 min. The split ratio was 100:1 and hydrogen was used as the carrier gas at 1.0 mL/min. FAME standards were used to identify sample FAME (Nu-Chek-Prep, Elysian, MN).
Statistical analyses.
Fatty acid composition data were analyzed statistically by the General Linear Model procedure of SAS (SAS Institute, Cary, NC). For treatments A, B, C and D, a single-factor ANOVA was used to identify the effect of treatment. Differences between treatment means were identified using the PDIFF option of the LSMeans command. Linear contrasts were used to determine differences between treatments B and E, C and F, and D and G. Treatment effects and differences between means were considered significant when P < 0.05. Tumor incidence was compared by 
2 analysis using the Frequency procedure of SAS. Total tumor numbers were compared by frequency distribution analysis (19).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Modulation of mammary cancer risk.
Examination of the mammary carcinogenesis data indicated that there was a progressive numerical decline (P = 0.15) in tumor incidence with increasing dietary intake of cis-9, trans-11 CLA (Table 3; treatments A, B, C and D). It should be noted that in this design, the dietary CLA level ranged from 0.05 g/100 g in treatment A to 0.37 g/100 g in treatment D. This range is at the low end of the CLA dose-response curve based on our historical data. Thus, the present finding is not unexpected. In contrast, the reduction in tumor incidence was more pronounced with increasing dietary VA (treatments E, F and G). Against this backdrop of the small increases in CLA, there was a distinct inhibitory response to VA that was dose dependent. The effect of VA was magnified in this experiment because the dose range was broadened compared with that of CLA; additionally, the entire dose range of VA was shifted a bit more to the right. The total numbers of tumors for each group were also examined. It was evident that the tumor yield data closely paralleled the tumor incidence data, thus further confirming the consistency of the results (Table 3).
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The fatty acid composition was determined for liver, plasma and mammary fat pad (Tables 4,5 and 6, respectively). The proportion of most fatty acids was similar for treatments A, B, C and D, whereas tissue and plasma concentrations of cis-9, trans-11 CLA increased with increasing dietary intake of cis-9, trans-11 CLA (Fig. 1). The liver concentration of cis-9, trans-11 CLA was increased >100% across the range of treatments A to D. The fatty acid concentration of cis-9, trans-11 CLA in both plasma and mammary fat pad was increased by only 38% when treatment A was compared with treatment D. In each tissue, a trend of increasing tissue cis-9, trans-11 CLA was observed with increasing dietary cis-9, trans-11 CLA (Fig. 1; bars corresponding to treatments A, B, C and D). The liver lipid concentration of several (n-3) fatty acids was also increased (Table 4; 20:5, 22:5, 22:6), but the basis is unknown.
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The contribution of dietary VA to tissue cis-9, trans-11 CLA was compared in liver, plasma and mammary fat pad (Fig. 2). To provide perspective, the relationship between VA and cis-9, trans-11 CLA in the diet was also included (Fig. 2, insert). The individual data points for liver, plasma and mammary fat pad from all treatments are shown with their corresponding regression line. Within each tissue, increasing the supply of VA linearly increased cis-9, trans-11 CLA concentration. The regression lines show the relative conversion of VA to cis-9, trans-11 CLA and the increasing concentration of cis-9, trans-11 CLA when comparing the diet with liver, liver with plasma, and finally the accumulation of cis-9, trans-11 CLA in the mammary fat pad. There was a relative increase in the proportion of VA converted to cis-9, trans-11 CLA over the progression from diet to mammary fat pad. The substantial difference in slope between liver and plasma would presumably reflect endogenous synthesis of cis-9, trans-11 CLA by hepatic 9-desaturase.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The effect of CLA on cancer has been investigated extensively using animal models, and cis-9, trans-11 CLA has proven particularly effective in preventing mammary cancer [for reviews, see (1,2)]. The mammary gland consists largely of adipocytes and these cells store large amounts of neutral lipids. CLA appears to be preferentially deposited into triglycerides (23), thus explaining its accumulation in the mammary gland. Dietary cis-9, trans-11 CLA was shown previously to have direct effects on mammary epithelial cells, including decreased proliferation and induction of apoptosis (24–27). Recently, dietary cis-9, trans-11 CLA was also shown to prevent the conversion of mammary stromal stem cells to endothelial cells, suggesting a possible role of cis-9, trans-11 CLA in the inhibition of angiogenesis (28).
The relationship of cis-9, trans-11 CLA and mammary cancer protection in humans has been examined through epidemiologic studies and results have been inconclusive. Aro et al. (29) found that serum cis-9, trans-11 CLA was significantly lower in breast cancer cases than controls in postmenopausal women and inferred that the CLA in dairy products could play a protective role against breast cancer. However, Chajés et al. (30) observed no difference in the breast adipose tissue concentration of cis-9, trans-11 CLA between breast cancer cases and controls. Voorrips et al. (31) used a food-frequency questionnaire to determine intakes of cis-9, trans-11 CLA and reported a significant relationship between cis-9, trans-11 CLA and breast cancer incidence (risk ratio of 1.24 after adjusting for known risk factors). However, the fatty acid data used in that study were criticized by others (32). Overall, these limited investigations provide no clear indication of a role for cis-9, trans-11 CLA in the prevention of breast cancer in humans. In general, differences in the intake of cis-9, trans-11 CLA between cases and controls, if available, are consistently small and may have been inadequate to observe an effect. The present study (Table 3) and Ip’s previous work with the rat model (20,33) demonstrated that there might be a threshold level of CLA for the manifestation of the cancer inhibitory effect. Furthermore, many factors influence breast cancer risk and the ability of cis-9, trans-11 CLA to alter risk may be dependent on the outcome of genetic and environmental interactions unique to different populations.
The labeling of the trans fatty acid (TFA) content of foods has received renewed attention because of the relationship of dietary intake with increases in plasma LDL cholesterol and the risk of coronary heart disease (34). Belury (35) challenged the appropriateness of grouping all TFA into a single entity for food labeling and used CLA isomers as examples of TFA for which beneficial effects have been identified. The present study demonstrates the beneficial effects of cis-9, trans-11 CLA on tumorigenesis in a rodent model, and further indicates that certain trans octadecenoic acid isomers can also have beneficial effects. Food products containing partially hydrogenated vegetable oils are the major dietary source of TFA in the United States (
90% of total). These are predominantly trans-18:1 acids, and the partial hydrogenation of vegetable oil produces a Gaussian distribution of trans 18:1 isomers that centers on trans-9, trans-10, and trans-11 isomers (36,37). The remainder of dietary TFA comes from food products derived from ruminants, and in this case, the major isomer is VA (36). The present study demonstrates that dietary VA has clear benefits in reducing mammary tumors either though direct action or via its use for endogenous synthesis of CLA. Interestingly, epidemiologic studies have observed a relationship between coronary heart disease risk and dietary intake of TFA from vegetable sources, but no such relationship exists for TFA intake from animal derived foods (38–40).
CLA represents a functional food component because it is present in ruminant fats, and studies with experimental models have identified a number of positive health effects associated with increased CLA intake. Chemically prepared CLA is available as a dietary supplement, and these products contain several CLA isomers. Although some of these formulations are of dubious quality (41), for the most part, they contain an approximately equal proportion of cis-9, trans-11 CLA and trans-10, cis-12 CLA as the major ingredients. Recently, there have been two papers demonstrating that trans-10, cis-12 CLA, but not the cis-9, trans-11 isomer, induced hyperinsulinemia and insulin resistance in mice (42,43), and that trans-10, cis-12 CLA, but not a mixed isomer preparation of CLA, induced insulin resistance in obese men (44,45). These very new data confirm the safety of cis-9, trans-11 CLA, while suggesting that trans-10, cis-12 CLA should undergo additional study. The production of pure cis-9, trans-11 CLA pills for the marketplace may be economically unaffordable. On the other hand, VA/CLA-enriched functional food could be a viable way of delivering anticancer agents to the general public. As pointed out earlier, the food form of CLA is predominantly the cis-9, trans-11 isomer, and VA conversion to cis-9, trans-11 CLA via 9-desaturase has been shown to occur in humans (12–14). This is a vanguard preclinical study, which demonstrates the feasibility of this approach.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: CLA, conjugated linoleic acid; MNU, methylnitrosourea; TFA, trans fatty acid; VA, vaccenic acid.
Manuscript received 13 March 2003. Initial review completed 11 May 2003. Revision accepted 9 June 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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E. E. Mosley, B. Shafii{dagger}, P. J. Moate, and M. A. McGuire cis-9, trans-11 Conjugated Linoleic Acid Is Synthesized Directly from Vaccenic Acid in Lactating Dairy Cattle J. Nutr., March 1, 2006; 136(3): 570 - 575. [Abstract] [Full Text] [PDF]
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 J. K. Kay, W. J. Weber, C. E. Moore, D. E. Bauman, L. B. Hansen, H. Chester-Jones, B. A. Crooker, and L. H. Baumgard Effects of Week of Lactation and Genetic Selection for Milk Yield on Milk Fatty Acid Composition in Holstein Cows J Dairy Sci, November 1, 2005; 88(11): 3886 - 3893. [Abstract] [Full Text] [PDF]
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J. J. Loor, A. Ferlay, A. Ollier, K. Ueda, M. Doreau, and Y. Chilliard High-Concentrate Diets and Polyunsaturated Oils Alter Trans and Conjugated Isomers in Bovine Rumen, Blood, and Milk J Dairy Sci, November 1, 2005; 88(11): 3986 - 3999. [Abstract] [Full Text] [PDF]
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A. L. Lock, C. A. M. Horne, D. E. Bauman, and A. M. Salter Butter Naturally Enriched in Conjugated Linoleic Acid and Vaccenic Acid Alters Tissue Fatty Acids and Improves the Plasma Lipoprotein Profile in Cholesterol-Fed Hamsters J. Nutr., August 1, 2005; 135(8): 1934 - 1939. [Abstract] [Full Text] [PDF]
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 Q. Yang, R. Alemany, J. Casas, K. Kitajka, S. M. Lanier, and P. V. Escriba Influence of the Membrane Lipid Structure on Signal Processing via G Protein-Coupled Receptors Mol. Pharmacol., July 1, 2005; 68(1): 210 - 217. [Abstract] [Full Text] [PDF]
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 S. L. Archibeque, D. K. Lunt, C. D. Gilbert, R. K. Tume, and S. B. Smith Fatty acid indices of stearoyl-CoA desaturase do not reflect actual stearoyl-CoA desaturase enzyme activities in adipose tissues of beef steers finished with corn-, flaxseed-, or sorghum-based diets J Anim Sci, May 1, 2005; 83(5): 1153 - 1166. [Abstract] [Full Text] [PDF]
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A. L. Lock, B. A. Corl, D. M. Barbano, D. E. Bauman, and C. Ip The Anticarcinogenic Effect of trans-11 18:1 Is Dependent on Its Conversion to cis-9, trans-11 CLA by {Delta}9-Desaturase in Rats J. Nutr., October 1, 2004; 134(10): 2698 - 2704. [Abstract] [Full Text] [PDF]
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P. A. Masso-Welch, D. Zangani, C. Ip, M. M. Vaughan, S. F. Shoemaker, S. O. McGee, and M. M. Ip Isomers of Conjugated Linoleic Acid Differ in Their Effects on Angiogenesis and Survival of Mouse Mammary Adipose Vasculature J. Nutr., February 1, 2004; 134(2): 299 - 307. [Abstract] [Full Text] [PDF]
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