Characterization of the Heregulin-Stimulated Activation of the Neu/ErB2 Tyrosine Kinase and its Involvement in Breast Cancer.

In this progress report, we describe work during the past year 71596-71597 in studying different aspects of the signaling pathways initiated by the EGF receptor and the related NeuErbB2 tyrosine kinase. We describe a novel mechanism for growth factor signaling where growth factor-stimulated dimerization events e.g. between the EGF receptor and Neu or between Neu and ErbB3 are transient and give rise to secondary receptor dimers. We also have obtained increasing evidence for the importance of two new signaling molecules, the c-Cbl protein and an 18 kDa splicing factor in the actions of the EGF receptor and Neu. In the coming year, we intend to extend these studies and identify and characterize signaling molecules that are activated in human breast cancer cells following primary and secondary receptor dimerization events. We also will determine whether the Cbl proto-oncogene product serves to interface the EGF receptor with the Cdc42 GTP-binding protein in breast cancer cells and how the splicing factor, CBP2O, is activated by heregulin. We also will determine if identical signaling pathways are operating in dog mammary carcinomas as an important step toward validating this system as a model for human breast cancer.