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Interaction of Dietary Fat and the Thymus in the Induction of Mammary Tumors by 7,12-Dimethylbenz(A)Anthracene1

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Interaction of Dietary Fat and the Thymus in the Induction of Mammary Tumors by 7,12-Dimethylbenz(A)Anthracene1 [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 host, specifically an elevation of serum prolactin levels, might be responsible for this effect (11, 34). Other possibilities The interaction of dietary fat and the thymus in the induction include an effect of dietary fat on the immune system (20, 22, of mammary tumors by dimethylbenz(a)anthracene has been 43), prostaglandins (30), or through maintenance and induction examined in female Sprague-Dawley rats. In these experi of prolactin receptors (42). ments, rats fed diets of 0.5% (low fat), 5% (normal fat), or 20% There is some experimental evidence which indicates that (high fat) corn oil from weaning (21 days of age) were thymec- the thymus can modulate mammary tumorigenesis. For exam tomized or sham thymectomized at 35 days of age and were ple, neonatal thymectomy has been shown to decrease the given 5 mg of dimethylbenz(a)anthracene at 55 days of age. incidence and increase the latency period of spontaneous (58), Thymectomy exerted a protective effect in rats fed low and transplantable (3), and chemical- or virus-induced mammary normal fat diets, and this was not reversed by Thymosin Frac tumors (28, 44, 45, 53, 55, 56, 60, 66). In addition, the tion V. In high fat-fed rats, tumorigenesis was increased com incidence of mammary tumors is decreased in mice treated pared to the low fat groups, and in addition, the protective with antithymocyte serum (5). Furthermore, it has been ob effect of thymectomy was absent. This differential effect of served clinically that patients with myasthenia gravis have a thymectomy could not be explained on the basis of changes in high incidence of breast cancer and that the incidence is prolactin concentration, since prolactin levels were decreased dramatically reduced in patients who have undergone thymec in all dietary groups. Neither diet nor thymectomy affected tomy (50, 51 ). corticosterone levels or the estrus cycle of mature rats. Periph In this paper, we have examined the interaction between eral blood lymphocytes were, however, decreased by both dietary fat and the thymus on the induction of mammary tumors thymectomy and increasing the fat content of the diet. It is by DMBA.5 An initial experiment demonstrated that tumor in hypothesized that the promoting effect of dietary fat on dimeth- cidence was markedly reduced in thymectomized rats fed ylbenz(a)anthracene-induced mammary tumorigenesis is me laboratory chow, and subsequent experiments were under diated via the immune system, although a role for the endocrine taken to see if thymectomy would alter the effectiveness of system still cannot be ruled out. dietary fat as a promoter of DMBA-induced mammary carci nogenesis. We also investigated the ability of Thymosin Frac INTRODUCTION tion V to reverse the effects of thymectomy. Recent observations support an important role for diet in the MATERIALS AND METHODS etiology of breast cancer. In particular, epidemiological studies have shown that there is a positive association between the Animals and Treatment. Female Sprague-Dawley rats (Charles incidence and mortality of breast cancer in women and the River Breeding Laboratories, Inc., Wilmington, Mass.) were housed in a temperature (22°) and light-controlled (12 hr of light and 12 hr of intake of dietary fat (1, 7, 19, 24, 26). This correlation has been supported by a large number of animal studies which dark) room with food and water available ad libitum. demonstrate an increased incidence of both spontaneous and In the initial experiment, rats were fed laboratory chow (Teklad, carcinogen-induced mammary tumors in rodents fed diets rich Madison, Wis) throughout the course of the experiment. They were thymectomized or sham thymectomized at 34 to 36 days of age and in fat, especially polyunsaturated fat (9, 10, 31, 34, 41, 62, were given a single i.g. intubation of 10 mg of DMBA (Sigma Chemical 65). The evidence strongly suggests that dietary fat acts at the Co., St. Louis, Mo.) dissolved in corn oil at a concentration of 10 mg/ promotional stage of carcinogenesis (8, 31-33), and it has ml at 50 to 55 days of age. Thymectomy was performed by making a been proposed that a change in the hormonal environment of midline longitudinal incision in the area above the sternum, separating the fascia to expose the thymus, and then aspirating the thymic lobes 1 This work was supported by Grants CA-13038 and CA-24538 from the through a glass cannula using gentle manipulation and constant suc National Cancer Institute. Parts of it are from a thesis which was submitted to the tion. The site was inspected for residual thymic tissue before closure. Faculty of the Roswell Park Division of the Graduate School of the State University Sham-thymectomized rats were opened in the same way, but the 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 incision was closed without removal of the thymic lobes. (35). In the first dietary fat experiment, hereafter called Experiment 1, rats 2 Present address: Department of Nutrition and Food Science, Massachusetts were placed on a diet of either 0.5% (low fat) or 20% (high fat) corn oil Institute of Technology, Cambridge, Mass. 02139. 3 Recipient of National Research Service Award (1 F32 AM 06131). Present starting at weaning (21 days of age). The composition of the diets is address: Laboratory of Human Reproduction and Reproductive Biology, Harvard given in Table 1. Within each dietary group, the rats were either Medical School, Boston. Mass. 02115. thymectomized or sham thymectomized at 35 days of age and were * To whom requests for reprints should be addressed, at Department of Experimental Therapeutics, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, N. Y. 14263. 5 The abbreviations used are: DMBA, 7,12-dimethylbenz(a)anthracene; i.g., Received July 27, 1981 ; accepted December 18, 1981. intragastric. 1266 CANCER RESEARCH VOL. 42 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1982 American Association for Cancer Research. Dietary Fat, the Thymus, and Mammary Cancer given 5 mg DMBA (in 1 ml corn oil), as above, at 55 days of age. The afternoon of proestrus. In Experiment 2, neck blood was obtained after second dietary fat experiment (Experiment 2) was the same as the first decapitation of the rats and was collected in nonheparinized tubes. except that a third dietary group, 5% corn oil (normal fat), was also After centrifugation, the serum was stored at - 70°.Sacrifice was done added. In addition, half of the thymectomized rats on the 5% corn oil between the hr of 1 and 3 p.m., 160 to 180 days after DMBA admin diet received Thymosin Fraction V, 10 mg/kg ¡.p.,3 times per week istration and was done without regard to the stage of the estrus cycle. starting the day after thymectomy. Thymosin Fraction V was prepared Corticosterone in plasma (Experiment 1) or serum (Experiment 2) by Hoffman-La Roche Inc. (Nutley, N. J.) and was a generous gift of was measured by the procedure described by Henning (27). This assay Dr. Allan Goldstein, George Washington University Medical Center, is based on corticosterone binding to rat corticosteroid-binding globulin Washington, D. C. and is very sensitive if careful attention is paid to the rate and method Rats were weighed and palpated weekly for the presence of mam by which dextran-coated charcoal is added. mary tumors. Each tumor location was recorded, and the size was Estrus Cycle. For determination of proestrus in rats that were to be measured with a vernier caliper in 2 perpendicular dimensions. At bled for prolactin assay, rats were monitored for a minimum of 2 autopsy, the tumors were excised and weighed, fixed in buffered complete cycles. In addition, the effect of thymectomy and dietary fat formalin, and sectioned for histological examination. In Experiment 1, on the estrus cycle was determined in 10 rats from each group of the spleen, thymus (if present), liver, kidney, ovary, and uterus were Experiment 1. This was done starting at 160 days after DMBA admin removed and weighed at autopsy. In all experiments, completeness of istration. Vaginal smears were taken between 9 and 11 a.m. and were thymectomy was confirmed at autopsy. analyzed according to the method of Bukovsky era/. (6). This technique Prolactin Assay. Blood for prolactin assay was taken in the after uses a scale of 1 to 10, based on the number of different cell types noon (between 1 and 3 p.m.) of proestrus in order to catch the peak observed. To prevent introduction of bias, slides were examined blind, level of circulating prolactin. In Experiment 1, neck blood was collected without knowledge of dietary group or presence or absence of the into heparinized tubes after decapitation of unanesthetized rats and thymus. Animals were examined for 14 days. was centrifugea, and the plasma was stored at -70° until assay. WBC and Differential WBC Count. For determination of WBC count, Sacrifice was from 160 to 180 days after DMBA administration. In tail vein blood (20 /il) was diluted with 10ml Isoton (Coulter Diagnostics, Experiment 2, blood was drawn from the orbital sinus of rats lightly Hialeah, Fla).
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