Induction of Breast Cancer by Nitrosomethylurea in Rats of the Buffalo Strain: Frequent Association with Thyroid Disease*

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Abstract
Rats of the inbred Buffalo strain spontaneously develop a significant incidence (′9%) of thyroid disease, defined by elevated relative thyroid weight (RTW) and histological thyroiditis. We have previously found this thyroid disease to be accompanied by varying degrees of thyroid failure. In addition, Buffalo rats are highly susceptible to the induction of metastasizing breast cancer by N-nitrosomethylurea (NMU). The purpose of the present investigation was to determine whether NMU-induced breast carcinogenesis was associated with changes in the incidence or nature of thyroid-pituitary abnormalities in the treated animals compared to those in vehicleinjected or untreated controls. Female Buffalo rats, 50-55 days old, were given a single ip injection of NMU (10 mg/100 g). All of the treated rats developed breast cancer. Fifty percent (15 of 30) showed greatly elevated RTW, averaging 5 times the RTW of vehicle-injected controls. Moreover, histological changes analogous to those of human Hashimoto's roiditis were strongly correlated with elevated RTW. The remaining 50% of the NMUtreated, cancer-bearing Buffalo rats exhibited RTW only 1.1 times the control level and normal thyroid histology. By comparison with our earlier study of 200 untreated female Buffalo rats (2), NMU increased the incidence of thyroid disease almost 6-fold above the spontaneous incidence (50% vs. 9%). In 7% (10 of 15) of the NMU-treated Buffalo rats with thyroid disease, plasma TSH was elevated and plasma T.(was low or normal. These hormone patterns are consistent with those observed in humans with Hashimoto's thyroiditis. Administration of the same NMU regimen to outbred CD rats caused breast cancer in all treated animals. However, in sharp contrast to the goitrogenic effects seen in Buffalo rats, NMU caused only a trivial increase in RTW in the outbred rats, 1.2-fold above outbred control RTW. Moreover, no histological abnormalities were observed in the thyroids of the NMU-treated outbred rats. Additionally, these animals did not exhibit thehormone patterns of elevated TSH and low to normal Ti found in most of the treated Buffalo rats with high RTW. We conclude that NMU-induced carcinogenesis of the breast was associated with an increased incidence of thyroid disease in inbred Buffalo rats but not in outbred CD rats.

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