Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis

The neu (c-erbB-2, Her-2) protooncogene is amplified and overexpressed in 2 0-30% of human breast cancers. Although transgenic mouse models have illust rated the role of Neu in the induction of mammary tumors, Neu expression in these models is driven by a strong viral promoter of questionable relevanc e to the human disease. To ascertain whether expression of activated Neu un der the control of the endogenous promoter in the mammary gland could induc e mammary tumors we have generated mice that conditionally express activate d Neu under the transcriptional control of the intact endogenous Neu promot er, Expression of oncogenic neu in the mammary gland resulted in accelerate d lobuloalveolar development and formation of focal mammary tumors after a long latency period. However, expression of activated Neu under the normal transcriptional control of the endogenous promoter was not sufficient for t he initiation of mammary carcinogenesis. Strikingly, all mammary tumors bea r amplified copies (2-22 copies) of the activated neo allele relative to th e wild-type allele and express highly elevated levels of neu transcript and protein. Thus, like human erbB-2-positive breast tumors, mammary tumorigen esis in this mouse model requires the amplification and commensurate elevat ed expression of the neu gene.