Genetic modulation of neu proto-oncogene-induced mammary tumorigenesis.

Modulation of oncogene-induced carcinogenesis by secondary mutation or genetic background may be an important factor in determining the expression of the tumor phenotype. We have investigated the role of loss of function mutations and strain-specific genetic elements in the modulation of oncogene-induced breast cancer using a murine model. FVB female mice transgenic for the rat neu proto-oncogene [mouse mammary tumor virus (MMTV)-neu] developed mammary tumors between 7 and 12 months of age, whereas FVB x C57Bl/6 (F1) MMTV-neu mice had tumor latencies greater than 18 months. The expression level of the neu transgene was equivalent in tumor tissue from both FVB and F1 mice. Furthermore, increased tumor latency did not appear to be associated with a decrease in expression of the neu transgene in the normal mammary gland of F1 mice because immunohistochemical staining for neu expression in the mammary glands of 3-month-old virgin female mice revealed similar levels of protein expression in FVB and F1 animals. When F1 animals were backcrossed one generation onto the FVB strain ([FVB x B6] F1 x FVB), a subset of the resulting offspring developed tumors with a latency equivalent to that of the pure-strain FVB mice. Statistical analysis of the genetic variability in mammary tumor latency indicated that approximately three independent genes were involved in the latency effect. Interestingly, when tumor growth rates were compared in these same animals, F1 mice had significantly faster tumor growth rates compared with FVB mice.