ACCELERATION OF MAMMARY NEOPLASIA IN TRANSFORMING GROWTH-FACTOR-ALPHATRANSGENIC MICE BY 7,12-DIMETHYLBENZANTHRACENE

A mouse mammary tumor virus enhancer/promoter-transforming growth fact or alpha transgenic mouse model has been described in which mammary tu mors 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 dos e of DMBA (0.5 mg) dramatically accelerates mammary tumor formation wh en administered to 21- and 56-day-old virgin transgenic females compar ed to their nontransgenic littermates. The latency period for tumor fo rmation is significantly shorter in transgenic mice treated with DMBA at 56 days compared to transgenic mice treated with DMBA at 21 days wh en results are analyzed by time from DMBA administration. To determine whether differences in the proliferative state of the mammary gland m ay contribute to these findings, bromodeoxyuridine incorporation was e xamined 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 mar ked increase in bromodeoxyuridine incorporation in the epithelial cell s comprising the smaller ducts of 56-day-old transgenic mice compared to their nontransgenic littermates. These data indicate an enhancing i nteraction between a growth factor and a genotoxic carcinogen in mamma ry tumorigenesis and provide evidence that the transforming growth fac tor alpha transgene acts as a tumor promoter in this experimental mode l.