Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors.

摘要: Amplification of the Neu/c-erbB-2 receptor tyrosine kinase has been implicated as an important event in genesis human breast cancer. Indeed, transgenic mice bearing either activated form neu or wild-type proto-oncogene under transcriptional control mouse mammary tumor virus promoter-enhancer frequently develop carcinomas (L. Bouchard, L. Lamarre, P. J. Tremblay, and Jolicoeur, Cell 57:931-936, 1989; C. T. Guy, M. A. Webster, Schaller, Parson, R. D. Cardiff, W. Muller, Proc. Natl. Acad. Sci. USA 89:10578-10582, 1992; E. Sinn, Wallace, K. Pattengale, Leder, 54:105-115, 1988). Induction tumors expressing Neu is associated with activation receptor's intrinsic activity (Guy et al., 1992). Here, we demonstrate that these occurs through somatic mutations located within transgene itself. Sequence analyses revealed they contain in-frame deletions 7 to 12 amino acids extracellular region proximal transmembrane domain. Introduction into a cDNA results increased transforming ability altered kinase. These observations suggest oncogenic tumorigenesis by mutation.