Mouse mammary glands in whole organ culture, previously demonstrated by others to undergo lobuloalveolar development, functional differentiation, and glandular involution, are transformable by carcinogenic aryl amines and amides and their derivatives. The transformation, which involves an escape from the hormonal controls of these processes, results in the formation of nodule-like alveolar lesions that are morphologically similar to presumptive preneoplastic lesions, termed hyperplastic alveolar nodules, which others have found to arise in mice during viral and chemical mammary tumorigenesis. The transformation system discriminates between carcinogens and noncarcinogens of analogous structures in the fluorenyl and naphthylenic chemical series, and is sensitively responsive to the presence of the amino or amide group or their derivatives. In a series of fluorenyl carcinogens, N-2-fluorenylacetamide displayed very high transforming activity > N-hydroxy-N-2-fluorenylacetamide (high activity), and > 2-fluoreneamine and 2-nitrofluorene (low activity). In contrast, the noncarcinogen, fluorene, had little if any transforming activity. The two naphthylenic carcinogens, 1-naphthylamine and 2-naphthylamine, both displayed moderate transforming activity, while the noncarcinogen, naphthalene, had no activity. Control glands treated only with the vehicle (dimethyl sulfoxide) were not transformed. Considerable structural changes at the cellular level were caused by the carcinogens, much less so by the noncarcinogens, and essentially none by the vehicle. It remains to be determined whether the glands transformed by these carcinogens can progress to tumors in vivo. The transformation by the carcinogenic aryl amines and amides and their derivatives (this report) and likewise the malignant transformation by the carcinogenic polycyclic aromatic hydrocarbons (Banerjee and coworkers, Proc. Am. Assoc. Cancer Res., 20: 153, 1979) suggest that mouse mammary gland in whole organ culture may be transformable by a broad spectrum of chemical carcinogens. The prospective linking of this transformation system to the considerable body of information presently known concerning these carcinogens may significantly increase the current understanding of the actions of chemical carcinogens on mammary gland and on epithelial tissues in general.
Supported in part by NIH Grants CA-21522 and CA-05945; Institutional Grants CA-09035, CA-06927, and RR-05539 from NIH; and an appropriation from the Commonwealth of Pennsylvania. Presented in part at the 18th Annual Meeting of the American Society for Cell Biology, San Antonio, Texas, November 6, 1978 (35).