Mammary neoplasia in animals: Pathologic aspects and the effects of contraceptive steroids

Abstract

The study of mammary neoplasms in animals and the use of experimental procedures to influence their development and progression has provided a great deal of insight into mammary carcinogenesis. Although the mouse, rat, cat, and dog develop mammary tumors with a sufficiently high frequency for use in experimental studies, none of these animals provide an ideal model for the study of the disease in women. Each species, including man, show certain unique aspects of the disease; yet, all share common features. Murine mammary tumors are primarily virus induced and provide an excellent laboratory animal model for studying genetic, immunologic, and hormonal interactions of virus-induced mammary tumors, a mechanism that could be operative in other species, including women. The development of mammary tumors in rats has been shown to be markedly altered by known chemical carcinogens. This property has favored the extensive use of this species in the testing of a variety of chemicals for carcinogenic properties. Mammary neoplasms in the cat perhaps most closely resemble the disease in women, but this model system has not been adequately exploited for this purpose. To effectively study the disease in cats would require long-term studies, since the mammary tumors occur in relatively old cats. The canine mammary neoplasm also occurs in older animals. Its use in comparative studies has been limited primarily to the carcinogenic testing of contraceptive steroids when it was recognized that this species develops a significant number of proliferative mammary lesions after 2-4 years of drug administration. Subsequent studies have clearly demonstrated that high doses of 17 α-hydroxyprogesterone derivatives and halogenated 19-nortestosterone derivatives produce a wide variety of proliferative lesions in the canine mammary gland which range from hyperplasias to mestastasizing neoplasms. Nonhalogenated derivatives of 19-nortestosterones (presently marketed compounds) have not been shown to produce excessive mammary nodules in the dog even when administered at the higher doses; however, reports in the literature describing the ongoing findings of long-term studies with these drugs are limited. Minimal chemical alteration ofte 19-nortestosterone derivatives such as halogenation at the 17th position is sufficient to make these compounds carcinogenic in the dog. Estrogens when administered alone do not produce excessive neoplasms in the dog. This is in contrast to the effects of estrogen in rodents, which at high doses, either alone or in combination with progestins, may promote the development of mammary tumors. Studies on the effects of contraceptive steroids on the mammary gland of nonhuman primates are incomplete. The significance of the intraductal hyperplasia observed microscopically in biopsies from nonhuman primates treated with 17α-hydroxyprogesterone derivatives and halogenated 19-testosterone derivatives is unknown, but it is of sufficient interest to warrant the continued observation of these animals for several years. It is inappropriate to extrapolate the findings in experimental animals directly to man, but in the absence of data on humans, animal studies must be used when it is necessary to make predictive judgments on factors that could influence the occurrence of a disease in man. In the case of contraceptive steroids, early animal studies indicated that some drugs could have carcinogenic properties. Since these drugs have now been administered to women for a number of years, future epidemiologic studies should permit the evaluation of their carcinogenic potential without reliance on animal data.