Normal and neoplastic mammary gland growth in MMTV/TGF α transgenic mice

Biochemical and dynamic changes of mammary glands in different reproductive states were studied in comparison with histological structures in female and male transgenic mice bearing human transforming growth factor α (TGF α) cDNA under the control of the mouse mammary tumour virus enhancer/promoter. Female and male F1 mice were divided into TGF α (+) and TGT α (-) groups according to the presence of TGF α gene at approximately 50 days of age. While there was little difference in mammary gland contents of DNA and RNA in females at 2 months of age, both nucleic acid contents were elevated markedly in TGF α (+) female mice with large variations at 4 months. These extremely high DNA and RNA contents in the TGF α (+) group declined to the level of the TGF α (-) group in the middle of pregnancy and at the end of pregnancy, respectively. Thymidine kinase (TK) activity in the mammary glands as an index of DNA synthesis was significantly higher in TGF α (+) mice than in TGF α (-) mice at both 2 and 4 months of age and the high TK in TGF α (+) mice also declined to the level of TGF α (-) mice with pregnancy. These biochemical and dynamic changes were in good accord with the histological changes of the glands; the glands of both groups consisted of fine ducts with small end-buds at 2 months of age, however, at 4 months, the glands of TGF α (+) mice were filled with outgrowth of acini or well developed lobulo-alveolar nodules, while the degree of this abnormal growth was various and the abnormality returned to the normal TGF α (-) level after the middle of pregnancy. TGF α mRNA expression was observed in the mammary glands of TGF α (+) females at any of the time points examined except at 2 months of age. TGF α (+) mice left as virgins developed mammary tumours afer 4 months of age and the incidence reached more than 80% at 8 months, but in TGF α (-) mice, none developed tumours. Associated with this, positive immunohistochemical staining of jun, fos and myc genes was observed only in the mammary glands of TGF α (+) mice. There was little difference between groups in the pattern of oestrous cycle and serum prolactin levels. All results indicate that TGF α induces abnormal mammary gland growth of mice with some and little modulation of oncogenes and mammotrophic hormones, respectively, and this effect of TGF α is counteracted by pregnancy. No difference was observed in any parameter of mammary gland growth between TGF α (+) and TGF α (-) male mice at 5 months of age, both of which showed no expression of TGF α mRNA in the glands.