The binding of growth factors and cytokines to their respective receptors regulates signal transduction cascades that are involved in the control of both cell growth and apoptosis. Overexpression of EGF receptor family members (ErbBs) has been observed in many human cancers, but the contribution of different ErbBs in tumor proliferation and chemosensitivity is unclear. Previous studies on breast cancer cells have revealed that ErbB1 (the EGF receptor) can confer resistance to chemotherapeutic drugs, whereas ErbB2 (Neu receptor) may allow for the rapid outgrowth of drug-resistant tumor cells. These data suggest that different ErbBs have different functions in promoting tumorigenesis. The goal of the present proposal is to define the signal transduction pathways controlled by ErbBs and to genetically and pharmacologically alter these pathways to enhance and/or stimulate apoptosis of breast cancer cells. The initial focus of this work will be to explore the relevance of the activities of potential anti-apoptotic pathways involving PI 3-kinase/Akt, ERKs, NF-kappaB and MEK kinase 1 (MEKK1). To address this goal, the following Specific Aims are proposed: 1) Define the contribution of specific signaling pathways in the survival of breast cancer cells. 2) Define the integration of Akt and MEKK1 signaling in the regulation of the core apoptotic machinery (Bcls, Apafs, caspases). 3) Evaluate the influence of the differential expression of ErbB family members in 32D cells on their ability to regulate signal transduction pathways that stimulate proliferation and/or suppress apoptosis in response to genotoxins and survival growth factor (IL-3) withdrawal. 4) Define the role of Cbl in ErbB1 signaling and the mediation of survival.
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