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Reports that protein kinase C is inhibited by sphingosine and other long-chain amines and the suggestion that promotion of mammary carcinogenesis by dietary fat is mediated by protein kinase C prompted us to investigate the effects of a long-chain amine, 1-octadecylamine, on mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene in rats fed a high-fat diet. Rats fed the amine sulfate at a level of 0.01% in a semipurified diet containing 20% corn oil developed more tumors than those fed the high-fat diet alone, although body weight gain was inhibited slightly. Rats fed the amine sulfate at 0.1% of the diet developed very few tumors compared with those fed either the high-fat diet or a low-fat diet containing 5% corn oil. At the higher level, the C18 amine also caused a marked inhibition of body weight gain.

Effects of dietary calcium on mammary carcinogenesis in rats were investigated because of evidence that calcium counteracts the promotion of colon cancer by dietary fat and because experimental diets for rats normally contain higher amounts of calcium and vitamin D than do human diets. Our earlier experiments indicated that yields of tumors induced in young, Sprague-Dawley rats by 7,12-dimethylbenz(a)-anthracene (DMBA) were higher when dietary calcium, phosphate, and vitamin D were decreased. Results of an experiment in which dietary amounts of calcium, phosphate, and vitamin D were varied independently suggested that phosphate and vitamin D have interactive effects with calcium. Another experiment in which dietary vitamin D alone was varied provided evidence that higher amounts inhibited tumorigenesis in the presence of low amounts of calcium and phosphate but the results with a high-calcium and -phosphate diet were inconclusive. The findings suggest that low amounts of dietary calcium and vitamin D and high amounts of phosphate increase susceptibility to DMBA-induced mammary neoplasia.

Evidence relating dietary fat to cancer at sites such as the breast and colon is provided by experiments showing that animals fed high-fat diets develop cancer at these sites more readily than do animals fed low-fat diets and by epidemiological data from different countries showing strong positive correlations between cancer incidence and mortality, and level of dietary fat. Experiments on animals have indicated that polyunsaturated vegetable oils promote cancer more effectively than do saturated fats or polyunsaturated fish oils, whereas in the epidemiological data, total dietary fat correlates with cancer incidence and mortality at least as well as does any particular type of fat. Case-control and cohort studies have not shown strong indications of a relationship between dietary fat and cancer, perhaps because of methodological difficulties inherent in such studies. The weight of evidence continues to indicate that long-term adherence to a low-fat diet can reduce the risk of some common types of cancer.

Evidence that dietary fat has an influence on carcinogenesis comes from both epidemiological data and experiments with animals. The experimental studies have indicated that dietary fat acts primarily as a promoter of carcinogenesis and that the effect depends on the type as well as the amount of fat in the diet. Vegetable oils containing polyunsaturated fatty acids of the linoleic acid family (n-6) have been shown to enhance mammary tumorigenesis, but a fish oil containing polyunsaturated fatty acids of the linolenic acid family (n-3) had an inhibitory effect at higher levels of intake. These and other findings suggest that the effect may be related to prostaglandins or other biologically active products of polyunsaturated fatty acids. Epidemiological data show a positive correlation between dietary fat and mortality from cancer at various sites, and this is supported by results of animal experiments in the case of colon cancer and pancreatic cancer as well as breast cancer. In the epidemiological data, cancer mortality shows strong positive correlations with total dietary fat and with animal fat, but not with fat derived from plants. Fats and oils used as spreads, cooking fats, and salad oils are the main source of fat in the American diet. Other major sources are meats and dairy products. Fat intake could probably be reduced substantially without serious deleterious effects, and this might help to decrease the risk of developing certain types of cancer.

The development of mammary tumors was examined in female noninbred Sprague-Dawley rats fed either a low-fat diet or high-fat diets containing different fats and fatty acid esters. Each rat was given 5 mg 7,12-dimethylbenz[a]anthracene by stomach tube 1 week before diets were introduced. Addition of 3% ethyl oleate (an ethyl ester of an unsaturated fatty acid) to a diet high in saturated fat (coconut oil) had no significant effect on tumor development, but the addition of 3% ethyl linoleate (an ethyl ester of a polyunsaturated fatty acid) increased the tumor yield to about twice that in rats fed either the high-saturated fat diet or a low-fat diet. Animals fed the high-saturated fat diet containing 3% ethyl linoleate developed as many tumors as those fed a 20% sunflower seed oil diet, though the sunflower seed oil diet contained about four times as much linoleate. Rats fed a high coconut oil diet containing 3% menhaden fish oil, which contains polyunsaturated fatty acids of the linolenate family (but having little linoleic acid), also developed as many tumors as those fed the 20% sunflower seed oil diet. These differences in mammary tumor yield could not be explained by alterations in the serum levels of prolactin, estrogen, or progesterone. However, the higher tumor yields were associated with increased unsaturation of mammary tissue phospholipids.

High fat diets promote the development of mammary tumors induced in rats by 7,12-dimethylbenz(a)anthracene (DMBA), and polyunsaturated fats are more effective than saturated fats. This difference is related to the linoleic acid content of polyunsaturated vegetable oils, but the amount of linoleate required for maximum tumor promotion appears to be higher than indicated by earlier experiments. Comparison of the effects of a polyunsaturated vegetable oil (corn oil) containing linoleate with a fish oil (menhaden oil) containing polyunsaturated fatty acids derived from linolenic acid showed that higher dietary levels of corn oil increased the yield of DMBA-induced mammary tumors, while corresponding levels of menhaden oil had an inhibitory effect. This is further evidence that promotion of mammary tumorigenesis by polyunsaturated vegetable oils may be mediated by prostaglandins or other biologically active eicosanoids derived from n-6 fatty acids.

High levels of dietary fat have been shown to promote the development of mammary tumors induced in rats by 7,12-dimethylbenz(alpha)anthracene, and polyunsaturated fats were found to be more effective than saturated fats. In further studies it was found that diets containing 3% sunflowerseed oil (polyunsaturated fat) and 17% beef tallow or coconut oil (saturated fats) enhance tumorigenesis as much as a diet containing 20% sunflowerseed oil. Rats on these diets developed at least twice as many tumors as those fed diets containing either 3% sunflowerseed oil or 20% of the saturated fats alone. These results are in accord with human epidemiological data which show that breast cancer mortality in different countries is positively correlated with total fat intake but not with intake of polyunsaturated fat. Total fat intake varies greatly in different countries, but most human diets probably contain levels of polyunsaturated fat at least equivalent to 3% sunflowerseed oil.

The effects of dietary fat on experimental mammary cancer have typically been observed in relatively young animals. However, in human populations, breast cancer incidence and mortality are highest in postmenopausal women. To develop an animal model that stimulates the human situation more closely, female Sprague-Dawley rats were given a relatively small dose (1.5 mg) of 7,12-dimethylbenz[a]anthracene (DMBA) at 50 days of age while on a semipurified diet containing 3% sunflower-seed oil. One week later, half of the 70 rats were transferred to a diet containing 20% sunflower-seed oil. Very few mammary lesions appeared until about 35 weeks after administration of DMBA, at which time palpable mammary nodules began to appear in many of the animals on the high-fat diet. More than half of the animals in this group had developed nodules by Week 41, whereas the other half of the animals on the low-fat diet developed nodules by Week 46. Rats on the high-fat diet gradually became much more obese than those on the low-fat diet and were significantly heavier at the time they developed lesions. The incidence of nodules continued to increase in both groups and reached 100% in the group fed the high-fat diet by Week 55, with a 70% incidence of adenocarcinomas. At this time, 79% of the animals on the low-fat diet had palpable nodules without a plateau in incidence being reached. On autopsy, adenocarcinomas were found in 57% of animals on the low-fat diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Young female Sprague-Dawley rats were administered 7,12-dimethylbenz(a)anthracene, and a week later the rats were transferred from commercial feed to a semipurified diet containing 20% corn oil. Eight weeks after receiving the carcinogen, half of the rats were changed to a fat-free diet to determine the effects on mammary tumor growth and development. After another 20 weeks, rats fed the fat-free diet had significantly fewer tumors per tumor-bearing rat and the tumors were smaller than those of rats that continued on the high-fat diet. Rats fed the fat-free diet weighed somewhat less, but showed no physical evidence of essential fatty acid deficiency. Tumors regressed in about half of the rats on the fat-free diet and in some cases became nonpalpable. After 28 weeks on this diet, the remaining rats were transferred back to the high-fat diet and subsequently showed a marked stimulation in tumor growth and development. This continued even after the rats were returned to the fat-free diet 8 weeks later, indicating that the tumors were no longer susceptible to the deprivation of dietary fat. The results of this study provide further evidence that dietary fat affects the promotional stage of mammary carcinogenesis.

Female Sprague-Dawley rats were given 7,12-dimethylbenz(a)anthracene at 50 days of age to induce mammary tumors, and beginning one week later were fed a high-fat, semipurified diet containing 20% sunflowerseed oil to promote tumor development. After another 7 weeks, when one third of the rats had palpable mammary tumors, the rats were randomly assigned to five groups of 31 animals each, with the same number of tumor-bearers in each group. One group was continued on the high-fat diet, another was given a fat-free diet, and the three remaining groups were fed diets containing 10% lard, butter, or coconut oil, respectively. During the next 29 weeks, rats fed the diets containing 0% or 10% fat developed significantly fewer tumors than those continued on the 20% fat diet. The diets containing 10% fat suppressed tumorigenesis at least as effectively as the fat-free diet. Rats fed the 10% butter and 10% lard diets had growth rates comparable to those fed the 20% sunflowerseed-oil diet throughout, and evidence of essential fatty acid deficiency was seen only in rats on the fat-free diet. These results provide additional evidence that high-fat diets promote development of mammary cancer and suggest that reducing the level of dietary fat might help to prevent the development and recurrence of breast cancer in humans.

The first evidence that dietary fat influences mammary carcinogenesis was provided by Tannenbaum, who showed that mice fed a high-fat diet developed spontaneous tumors more readily than those fed a low-fat diet. Similar observations have been made with various other animal models. Polyunsaturated vegetable oils enhance carcinogenesis more effectively than saturated fats, because of their higher linoleate content. Diets containing high levels of polyunsaturated fish oils do not stimulate carcinogenesis, however, perhaps because their polyunsaturated fatty acids belong mainly to the linolenate family. Dietary fat acts primarily as a promoting agent, but the exact mechanism is still unclear. The requirement for linoleate and the fact that the fat effect can be blocked by prostaglandin biosynthesis inhibitors suggests that it may be mediated by biologically-active compounds derived from linoleate. Other possibilities include changes in hormonal balance, alterations in the fatty acids of membrane lipids, effects on the immune system, modulation of intercellular communications, and metabolic alterations related to differences in fat and caloric intake. Interest in the role of dietary fat in mammary carcinogenesis has been greatly stimulated by epidemiological evidence of a strong, positive correlation between breast cancer and dietary fat. In these epidemiological data, total dietary fat shows a better correlation than fat from either plant or animal sources individually, and there is no apparent correlation with the polyunsaturated fatty acid content of the diet. Further studies are needed to investigate more thoroughly this apparent difference between experimental and epidemiological data.(ABSTRACT TRUNCATED AT 250 WORDS)

Female Sprague-Dawley rats were fed semipurified diets containing various fats, either alone or in combination, to provide different amounts of dietary fat and linoleic acid. One week before commencing the diets, each rat received an intra-gastric dose of the carcinogen 7,12-dimethylbenz[a]anthracene. Rats fed diets containing mixtures of 3% sunflower seed oil and 17% of either tallow or coconut oil developed twice as many tumors as those fed 3% sunflower seed oil or 20% of either saturated fat alone. Tumor yields in the rats fed these mixed-fat diets were comparable to those in rats fed a 20% lard diet, which provided about the same amount of linoleic acid. No further increase in tumor yield was observed in rats fed a 20% sunflower seed oil diet that contained more than five times as much linoleic acid. These results show that a certain amount of polyunsaturated fat, as well as a high level of dietary fat, is required to promote mammary carcinogenesis.

Mammary carcinoma was induced in female Nb rats by implanting pellets of estrone at 25-28 days of age, and prostatic cancer was induced in male rats of the same strain by repeatedly implanting pellets of testosterone propionate. Feeding semipurified diets containing either 3% or 20% corn oil did not significantly affect the incidence or yield of mammary tumors, although tumors tended to appear somewhat earlier in animals on the high-fat diet, confirming the report of Dunning et al. published nearly 40 years ago. The yield of prostatic tumors was too low to draw any conclusions with respect to dietary fat. Hormonally induced mammary tumors appear to be less responsive to dietary fat than those induced by commonly used chemical carcinogens.

This study was designed to test the influence of dietary calcium and vitamin D levels on the promotional effect of high-fat diets on chemically induced mammary carcinogenesis. In a small preliminary experiment (Experiment A), 40 female Sprague-Dawley rats, 43 days old, were randomly divided into 5 groups (8 rats/group) and fed a semipurified diet containing 3% sunflower seed oil (SF) by weight, 1.5 mg of calcium/kcal and 0.5 IU vitamin D/kcal of diet. After 1 week, each rat was given 2.5 mg of dimethylbenz(a)anthracene by gastric gavage. One week later, the animals were switched to 1 of 4 diets varying in fat (3 or 20% SF by weight), calcium (1.5 or 0.25 mg/kcal), vitamin D (0.5 or 0.05 IU/kcal), and phosphate or to a fifth diet containing 3% SF by weight, 0.1 mg of calcium/kcal and 0.05 IU of vitamin D/kcal. In all 5 diets, calcium:phosphate weight ratios were maintained at 1.2:1. In animals fed the high-fat diet, reduction of dietary calcium (1.5 to 0.25 mg/kcal) and vitamin D (0.5 to 0.05 IU/kcal) increased the incidence of mammary lesions from 37 to 75% and the total number of lesions from 4 to 16. A trend toward an increase in lesion weight and total lesion burden was also seen. To confirm these results, the experiment was repeated using the same protocol; 126 rats were divided into 6 groups, treated with dimethylbenz(a)anthracene, and fed the diets as described. A sixth diet was included that contained 20% SF by weight, 0.01 mg of calcium/kcal, and 0.05 IU of vitamin D/kcal. As for Experiment A, in animals fed the high-fat diet, reduction of dietary calcium (1.5 to 0.25 mg/kcal) and vitamin D (0.5 to 0.05 IU/kcal) resulted in an increase in total mammary lesions from 31 to 55, a significant increase in average lesion burden/rat with lesions (1.6 +/- 0.6 to 12 +/- 3 g), and a trend toward increasing weight of lesions. The effect was less obvious in animals fed the low-fat diet where, in both experiments, an increase in the incidence of mammary lesions was observed only when the dietary calcium was reduced from 1.5 to 0.1 mg/kcal. These data suggest that decreasing calcium and vitamin D increase the promoting effects of a high-fat diet on mammary tumorigenesis in the rat.

Analysis of epidemiological data and experiments with animals have provided evidence that dietary fat has an important influence on mammary cancer. Further epidemiological studies should be carried out to examine this relationship more fully, and additional experimental work is required to determine the mechanisms by which dietary fat influences mammary cancer in animals. Dietary carbohydrate and minor dietary components, such as retinoids and certain trace elements, have also been shown to influence mammary cancer in animals. Decreasing the fat content of the diet may offer a practical means of reducing mortality from breast cancer, which continues to be a major cause of death in many parts of the world.

The molecular phospholipid species of mammary tumors induced by 7,12-dimethylbenz[a]anthracene in rats that were fed diets containing 20 or 3% sunflower-seed oil and different levels of calcium were analyzed by high-pressure liquid chromatography. Twenty-seven molecular species of phospholipids were identified. Phosphatidylcholine was predominantly composed of palmitoyl-arachidonoyl (16:0-20:4) (17-21%), palmitoyl-oleoyl (16:0-18:1) (19-21%), stearoyl-arachidonoyl (18:0-20:4) (12-13%), and 1,2-dipalmitoyl (16:0-16:0) (10-14%) species. The major molecular species of phosphatidylethanolamine were 18:0-20:4 (37-39%) and 16:0-20:4 (10-11%). The composition of diacyl phosphatidylcholine and diacyl phosphatidylethanolamine molecular species from rat mammary tumors was not greatly affected by the different diets.

Promotion of carcinogenesis in rats by dietary fat depends on the amount and type of fatty acids ingested, mainly as triglycerides. A certain amount of essential fatty acid of the linoleate type (n-6) is required for promotion of mammary cancer and pancreatic cancer and probably also for colon cancer. Promotion is also enhanced by a high level of dietary fat, and this additional effect seems to be relatively independent of the type of fat. Saturated fatty acids, either medium or long chain, and cis and trans monoenoic fatty acids appear to have no specific promoting effects. Fish oils containing long-chain polyunsaturated fatty acids of the linolenate type (n-3) are inhibitory, and this may also be true for rapeseed oil high in erucic acid, a long-chain monoenoic fatty acid. The promoting action of dietary fat can be modified by other components of the diet, such as starch, sugar, and fiber. Promotion is also dependent on the length of time animals are exposed to the high-fat diet. The overall tumor yield can be decreased by reducing the level and degree of unsaturation of the dietary fat after a period of feeding a high polyunsaturated-fat diet.