[CANCER RESEARCH 42. 1266-1273, April 1982] 0008-5472/82/0042-OOOOS02.00 Interaction of Dietary Fat and the Thymus in the Induction of Mammary Tumors by 7,12-Dimethylbenz(a)anthracene1 David A. Wagner,2 Paul H. Naylor,3 Untae Kim, Wendy Shea, Clement Ip, and Margot M. Ip4 Department of Experimental Therapeutics, Grace Cancer Drug Center [D. A. W., P. H. N., W. S., M. M. I.], and Departments of Pathology [U. KJ and Breast Surgery [C. I.], New York State Department of Health, Roswe/l Park Memorial Institute, Buffalo, New York 14263 ABSTRACT 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 experi ments, rats fed diets of 0.5% (low fat), 5% (normal fat), or 20% (high fat) corn oil from weaning (21 days of age) were thymec- tomized 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 Frac tion V. In high fat-fed rats, tumorigenesis was increased com pared 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. Periph eral 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 dimeth- ylbenz(a)anthracene-induced mammary tumorigenesis is me diated via the immune system, although a role for the endocrine system still cannot be ruled out. INTRODUCTION Recent observations support an important role for diet in the etiology of breast cancer. In particular, epidemiological studies have shown that there is a positive association between the incidence and mortality of breast cancer in women and the intake of dietary fat (1, 7, 19, 24, 26). This correlation has been supported by a large number of animal studies which demonstrate an increased incidence of both spontaneous and carcinogen-induced mammary tumors in rodents fed diets rich in fat, especially polyunsaturated fat (9, 10, 31, 34, 41, 62, 65). The evidence strongly suggests that dietary fat acts at the promotional stage of carcinogenesis (8, 31-33), and it has been proposed that a change in the hormonal environment of 1 This work was supported by Grants CA-13038 and CA-24538 from the National Cancer Institute. Parts of it are from a thesis which was submitted to the Faculty of the Roswell Park Division of the Graduate School of the State University of New York at Buffalo, in partial fulfillment of the requirements for the degree of Master of Science (D. A. W.). A preliminary report of this work has been presented (35). 2 Present address: Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Mass. 02139. 3 Recipient of National Research Service Award (1 F32 AM 06131). Present address: Laboratory of Human Reproduction and Reproductive Biology, Harvard Medical School, Boston. Mass. 02115. * To whom requests for reprints should be addressed, at Department of Experimental Therapeutics, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, N. Y. 14263. Received July 27, 1981 ; accepted December 18, 1981. the host, specifically an elevation of serum prolactin levels, might be responsible for this effect (11, 34). Other possibilities include an effect of dietary fat on the immune system (20, 22, 43), prostaglandins (30), or through maintenance and induction of prolactin receptors (42). There is some experimental evidence which indicates that the thymus can modulate mammary tumorigenesis. For exam ple, neonatal thymectomy has been shown to decrease the incidence and increase the latency period of spontaneous (58), transplantable (3), and chemical- or virus-induced mammary tumors (28, 44, 45, 53, 55, 56, 60, 66). In addition, the incidence of mammary tumors is decreased in mice treated with antithymocyte serum (5). Furthermore, it has been ob served clinically that patients with myasthenia gravis have a high incidence of breast cancer and that the incidence is dramatically reduced in patients who have undergone thymec tomy (50, 51 ). In this paper, we have examined the interaction between dietary fat and the thymus on the induction of mammary tumors by DMBA.5 An initial experiment demonstrated that tumor in cidence was markedly reduced in thymectomized rats fed laboratory chow, and subsequent experiments were under taken to see if thymectomy would alter the effectiveness of dietary fat as a promoter of DMBA-induced mammary carci nogenesis. We also investigated the ability of Thymosin Frac tion V to reverse the effects of thymectomy. MATERIALS AND METHODS Animals and Treatment. Female Sprague-Dawley rats (Charles River Breeding Laboratories, Inc., Wilmington, Mass.) were housed in a temperature (22°) and light-controlled (12 hr of light and 12 hr of dark) room with food and water available ad libitum. In the initial experiment, rats were fed laboratory chow (Teklad, Madison, Wis) throughout the course of the experiment. They were thymectomized or sham thymectomized at 34 to 36 days of age and were given a single i.g. intubation of 10 mg of DMBA (Sigma Chemical Co., St. Louis, Mo.) dissolved in corn oil at a concentration of 10 mg/ ml at 50 to 55 days of age. Thymectomy was performed by making a midline longitudinal incision in the area above the sternum, separating the fascia to expose the thymus, and then aspirating the thymic lobes through a glass cannula using gentle manipulation and constant suc tion. The site was inspected for residual thymic tissue before closure. Sham-thymectomized rats were opened in the same way, but the incision was closed without removal of the thymic lobes. In the first dietary fat experiment, hereafter called Experiment 1, rats were placed on a diet of either 0.5% (low fat) or 20% (high fat) corn oil starting at weaning (21 days of age). The composition of the diets is given in Table 1. Within each dietary group, the rats were either thymectomized or sham thymectomized at 35 days of age and were 5 The abbreviations used are: DMBA, 7,12-dimethylbenz(a)anthracene; i.g., intragastric. 1266 CANCER RESEARCH VOL. 42 on June 15, 2015. © 1982 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from