Inappropriate activation of signaling pathways that are normally used for development or growth of tissues can contribute to the formation or progression of cancers. Receptor tyrosine kinases are a broad group of enzymes that have been shown to be particularly important in these functions. The ErbB family of receptors, are known to be regulated by ovarian steroids and are important for development of the mammary ductal tree. It is well known that these receptors contribute to the pathogenesis of carcinomas, especially those that originate in the breast epithelium. Although attention has been given to ErbB-2 which is overexpressed or overamplified in many human breast cancers, the functional significance of ErbB-3, which has the capacity to heterodimerize with ErbB-2, has not been adequately investigated. In one study, we are examining mouse tumors obtained from various transgenic and chemically-treated animals for activation of ErbB-3 and ErbB-2, as well as the expression of heregulin, an ErbB-3 ligand. Tyrosine phosphorylated forms of ErbB-2 and ErbB-3 were consistently found in extracts from tumors obtained from transgenic (e.g., MMTV-ErbB-2, MMTV-Wnt-1) but not in all chemically-induced tumors. Heregulin transcripts were found in all tumors. Western analyses of heregulin in extracts of mouse mammary tumor cell lines revealed immunoreactivity at ~ 45 kDa and at slightly greater than 100 kDa. In another study, we are attempting to understand more about the functional properties of ErbB-3 in mammary cells, especially those linked to cell signaling and gene expression. Human mammary epithelial cells immortalized with telomerase have been stably transfected with ErbB-3 cDNA. These cells will be compared to the parent cell line for changes in signaling patterns, growth, gene expression, and the capacity to differentiate.
