Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer

To assess the importance of Neu activation during mammary tumorigenesis, al tered receptors harboring in-frame deletions within the extracellular domai n were expressed in transgenic mice. Females from several independent lines develop multiple mammary tumors that frequently metastasize to the lung. T umor progression in these strains was associated with elevated levels of ty rosine-phosphorylated Neu and ErbB-3, Consistent with these observations, a survey of primary human breast tumors revealed frequent co-expression of b oth erbB-2 and erbB-3 transcripts. The ability of altered Neu receptors to induce mammary tumorigenesis in transgenic mice prompted us to examine whet her similar mutations occurred in ErbB-2 during human breast cancer progres sion. Interestingly, an alternatively spliced form of erbB-2, closely resem bling spontaneous activated forms of neu, was detected in human breast tumo rs. The ErbB-2 receptor encoded by this novel transcript harbors an in-fram e deletion of 16 amino acids in the extracellular domain and can transform Rat-1 fibroblasts. Together, these observations argue that co-expression of ErbB-2 and ErbB-3 may play a critical role in the induction of human breas t tumors, and raise the possibility that activating mutations in the ErbB-2 receptor may also contribute to this process.