Germ-line expression of an oncogenic erbB2 allele confers resistance to erbB2-induced mammary tumorigenesis.

We have previously shown that mammary epithelial specific expression of the activated erbB2 allele under the control of the endogenous promoter in mice resulted in the formation of mammary adenocarcinomas. To assess whether mammary tumorigenesis in this model is influenced by the developmental window of expression, we generated mice that expressed the activated erbB2 allele in the germ line. Although we were able to derive viable transgenic mice that were heterozygous for the activated erbB2 allele, mice homozygous for the activated erbB2 allele died at 12.5 days of embryogenesis. These two separate lines of mice expressed activated erbB2 at equal levels in the mammary gland. Surprisingly, unlike the tumor-prone mice expressing activated ErbB2 in the mammary epithelium, mice with the germ-line erbB2 allele failed to develop tumors. Gene expression analysis of the preneoplastic mammary glands revealed that there were a number of luminal epithelial markers expressed at higher levels in the tumor-prone mice. These data suggest either an expansion of a susceptible population in the tumor-prone mice or the loss of this population in the tumor-resistant mice. Taken together, these observations suggest that the temporal pattern of expression of activated ErbB2 is a critical determinant in mammary tumorigenesis. These results strongly suggest that there are feedback mechanisms present that can compensate for the expression of a potent oncogene.