Acceleration of mammary neoplasia in transforming growth factor alpha transgenic mice by 7,12-dimethylbenzanthracene

A mouse mammary tumor virus enhancer/promoter-transforming growth factor alpha transgenic mouse model has been described in which mammary tumors develop (Y. Matsui et al., Cell, 61: 1147-1155, 1990). In Line 29, spontaneous mammary tumors do not develop before 300 days of age in virgin females. Herein, Line 29 virgin females and their nontransgenic littermates have been treated with 7,12-dimethylbenzanthracene (DMBA) at varying dosages and times. Orogastric instillation of a single dose of DMBA (0.5 mg) dramatically accelerates mammary tumor formation when administered to 21- and 56-day-old virgin transgenic females compared to their nontransgenic littermates. The latency period for tumor formation is significantly shorter in transgenic mice treated with DMBA at 56 days compared to transgenic mice treated with DMBA at 21 days when results are analyzed by time from DMBA administration. To determine whether differences in the proliferative state of the mammary gland may contribute to these findings, bromodeoxyuridine incorporation was examined in the mammary glands of untreated 21- and 56-day-old mice. No differences in bromodeoxyuridine incorporation were detected between 21-day-old transgenic and nontransgenic mice. However, there was a marked increase in bromodeoxyuridine incorporation in the epithelial cells comprising the smaller ducts of 56-day-old transgenic mice compared to their nontransgenic littermates. These data indicate an enhancing interaction between a growth factor and a genotoxic carcinogen in mammary tumorigenesis and provide evidence that the transforming growth factor alpha transgene acts as a tumor promoter in this experimental model.