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 result further demonstrated that the vast majority of nitrosomethylurea (NMU)-induced rat mammary tumors with Ha-ras-1 oncogenes arose from these pre-existing mutants. We therefore investigated whether Ha-ras-1 mutants acquired a selective growth advantage in vivo in the absence of NMU exposure. Our results indicated that between the ages of 50 and 570 days, the total number mammary epithelial cells per rat increased approximately 5 fold (from 3.7x10(7) to 1.8x10(8) cells), while the average number of Ha-ras-1 mutants per rat increased approximately 25 fold (from 160 to 4000 cells). Thus, the mutants acquired a measurable (5-fold) growth advantage in vivo. To determine if the growth of these mutants contributed to spontaneous mammary carcinogenesis, we measured Ha-ras-1 mutant fractions in 26 tumors from untreated F344 rats. The assay failed 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 realized only under certain specific physiological conditions, such as exposure to a carcinogenic dose of NMU exposure.