Mutational activation of the Neu receptor tyrosine kinase during mammary tumorigenesis in the transgenic mice

Abstract

<p>Overexpression of the Neu/ErbB-2 receptor has been implicated in the genesis of human breast cancer. Indeed, transgenic mice expressing the neu proto-oncogene develop focal tumors arising next to hyperplastic mammary epithelium after a long latency period. Induction of mammary tumors in these mice was associated with activation of the receptor's tyrosine kinase activity. In this thesis, I demonstrate that oncogenic activation of the Neu tyrosine kinase occurs through somatic mutation in a large proportion of MMTV/wild-type neu mammary tumors. These alterations occur within the neu transgene itself and comprise both in-frame deletions and insertions within the receptor's extracellular domain. These mutations promote constitutive dimerization of Neu through the formation of intermolecular disulfide bonds. To directly assess the importance of Neu activation during mammary tumorigenesis, I have expressed two such altered receptors in the mammary epithelium of transgenic mice. Females from several independent lines develop multiple mammary tumors that frequently metastasize to the lung. Interestingly, an alternatively spliced form of erbB - 2 , closely resembling spontaneously activated forms of neu , was detected in human breast cancers. The ErbB-2 receptor encoded by this novel transcript lacks 16 amino acids of the extracellular domain and transforms Rat-1 fibroblasts. These observations raise the possibility that activating mutations in the ErbB-2 receptor may also contribute to human breast cancer progression.</p>