The carcinogen-induced rat mammary carcinoma model, developed a quarter of a century ago by Dr. Charles Brenton Huggins, is today the standard laboratory animal model in the study of human breast cancer. This model has a number of features that make it particularly attractive to the experimental oncologist, e.g., tumor induction ease and reliability, organ site specificity, tumors of ductal origin, tumors of predominantly carcinomatous histopathological characteristics, tumors of varying growth factor and/or hormone responsiveness, and the potential to examine tumor initiation and promotion processes. Since the development of this model, an extensive literature describing the biological behavior and responsiveness of these tumors has been provided. The purpose of this communication is to condense, summarize, and integrate this vast literature into a single review with the intent on facilitating information acquisition and conceptualism by both the new and the established experimental oncologist. In addition, and equally important, this communication is a tribute to Dr. Huggins, whose pioneering efforts in the development of this model and whose scientific contributions and dedication to the oncological sciences in general have made an important and lasting impact on us all.

https://cancerres.aacrjournals.org/content/canres/45/8/3415.full.pdf

Host Factors Affecting the Growth of Carcinogen-induced Rat Mammary Carcinomas: A Review and Tribute to Charles Brenton Huggins

We have extracted from the literature data from 100 animal experiments, involving 7838 rats and mice, which compared the effects of different levels of dietary fat and/or calorie intake on the development of mammary tumors. Both higher calorie intake (P less than 0.0001) and higher fat intake (P less than 0.0001) independently increased mammary tumor incidence in Sprague-Dawley rats and in mice, as judged from analyses combining ad libitum feeding experiments and restricted feeding experiments. The effect of fat was two thirds the magnitude of the calorie effect in both Sprague-Dawley rats and mice. In ad libitum feeding experiments, a modest but significant (P less than 0.0001) average increase in body weight was found in animals fed high fat diets. However, these differences in body weight did not correspond to differences in mammary tumor incidence. The effect of log body weight on the log odds of tumor incidence was not significant (P = 0.16), while dietary fat intake significantly increased tumor incidence (P less than 0.0001). The collection of animal experimental data supports the hypothesis that, in mammary tumor development, there is a specific enhancing effect of dietary fat, as well as a general enhancing effect of calories.

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Analysis of Dietary Fat, Calories, Body Weight, and the Development of Mammary Tumors in Rats and Mice: A Review

We performed a meta-analysis on data extracted from 97 reports of experiments, involving a total of 12,803 mice or rats, studying the effect on mammary tumor incidence of different types of dietary fatty acids. Fatty acids were categorized into saturated, monounsaturated, n-6 polyunsaturated, and n-3 polyunsaturated. We modeled the relation between tumor incidence and percentage of total calories from these fatty acids using conditional logistic regression and allowing for varying effects between experiments, and for each fatty acid we estimated the effect of substituting the fatty acid calories for nonfat calories. Our results show that n-6 polyunsaturated fatty acids (PUFAs) have a strong tumor-enhancing effect and that saturated fats have a weaker tumor-enhancing effect. The n-3 PUFAs have a small protective effect that is not statistically significant. There is no significant effect of monounsaturated fats. n-6 PUFAs have a stronger tumor-enhancing effect at levels under 4% of total calories, but an effect is still present at intake levels greater than 4% of calories. In addition, when the intake of n-6 PUFAs is at least 4% of calories, the n-6 PUFA effect remains stronger than the saturated fat effect.

https://cancerres.aacrjournals.org/content/canres/57/18/3979.full.pdf

Effect of Different Types and Amounts of Fat on the Development of Mammary Tumors in Rodents: A Review

Biological Responses in Cancer

The mammary tumor-promoting effect of a high-fat diet containing 20% evening primrose oil (PO) was compared to that of a 20% corn oil (CO) diet. Mammary tumors were induced in female Sprague-Dawley rats using 10 mg (Study 1) and 5 mg (Study 2) 7,12-dimethylbenz(a)anthracene (DMBA). The 10 mg dose of DMBA gave a total mammary tumor incidence of 47% in rats fed the PO diet and 80% for those fed the CO diet. When only adenocarcinomas were counted, the malignant mammary tumor incidences were 41% in rats fed the PO diet and 73% in rats fed the CO diet. In a second study using 5 mg DMBA to induce mammary tumors, total tumor incidences were 50% for PO-fed rats and 63% for those receiving a CO diet. Again, when only adenocarcinomas were counted, tumor incidences were 27% for PO- and 63% for CO-dieted rats. Analysis of plasma fatty acid profiles indicated that animals fed a 20% PO diet showed significant increases in 18∶3 and 20∶4 fatty acids and significant decreases in 16∶0 and 18∶1 compared to animals fed a 20% CO diet. These results indicate that the mammary tumor promoting effect of a diet containing 20% fat can be diminished by substituting PO for CO. Moreover, the promoting effect on mammary cancer by a high-fat diet could be depressed by feeding a source of γ-linolenic acid (GLA).

Effects of dietary primrose oil on mammary tumorigenesis induced by 7,12-dimethylbenz(a)anthracene.

The interaction of dietary fat and the thymus in the induction of mammary tumors by dimethylbenz(a)anthracene has been examined in female Sprague-Dawley rats. In these experiments, rats fed diets of 0.5% (low fat), 5% (normal fat), or 20% (high fat) corn oil from weaning (21 days of age) were thymectomized or sham thymectomized at 35 days of age and were given 5 mg of dimethylbenz(a)anthracene at 55 days of age. Thymectomy exerted a protective effect in rats fed low and normal fat diets, and this was not reversed by Thymosin Fraction V. In high fat-fed rats, tumorigenesis was increased compared to the low fat groups, and in addition, the protective effect of thymectomy was absent. This differential effect of thymectomy could not be explained on the basis of changes in prolactin concentration, since prolactin levels were decreased in all dietary groups. Neither diet nor thymectomy affected corticosterone levels or the estrus cycle of mature rats. Peripheral blood lymphocytes were, however, decreased by both thymectomy and increasing the fat content of the diet. It is hypothesized that the promoting effect of dietary fat on dimethylbenz(a)anthracene-induced mammary tumorigenesis is mediated via the immune system, although a role for the endocrine system still cannot be ruled out.

https://cancerres.aacrjournals.org/content/canres/42/4/1266.full.pdf

Paul H. Naylor

Papers

Interaction of Dietary Fat and the Thymus in the Induction of Mammary Tumors by 7,12-Dimethylbenz(a)anthracene