HA-RAS-1 ONCOGENE MUTATIONS IN MAMMARY EPITHELIAL-CELLS DO NOT CONTRIBUTE TO INITIATION OF SPONTANEOUS MAMMARY TUMORIGENESIS IN RATS

We have previously shown that oncogenic GGA to GAA mutations in codon 12 of the Ha-ras-1 gene arise spontaneously during normal development of the mammary epithelium of female Fischer 344 (F344) rats, Our resul t further demonstrated that the vast majority of nitrosomethylurea (NM U)-induced rat mammary tumors with Ha-ras-1 oncogenes arose from these pre-existing mutants, We therefore investigated whether Ha-ras-1 muta nts acquired a selective growth advantage in vivo in the absence of NM U exposure, Our results indicated that between the ages of 50 and 570 days, the total number mammary epithelial cells per rat increased simi lar to 5 fold (from 3.7x10(7) to 1.8x10(8) cells), while the average n umber of Ha-ras-1 mutants per rat increased similar to 25 fold (from 1 60 to 4000 cells). Thus, the mutants acquired a measurable (5-fold) gr owth advantage in vivo. To determine if the growth of these mutants co ntributed to spontaneous mammary carcinogenesis, we measured Ha-ras-1 mutant fractions in 26 tumors from untreated F344 rats. The assay fail ed to detect Ha-ras-1 mutant fractions higher than 10(-3), indicating that in the mammary epithelium, the activating mutation of the Ha-ras- 1 gene is a conditional oncomutation, whose oncogenic potential is rea lized only under certain specific physiological conditions, such as ex posure to a carcinogenic dose of NMU exposure.