The polypeptide mitogen Epidermal Growth Factor (EGF) stimulates quiescent cell cultures to initiate DNA synthesis and cell division. Binding of EGF to specific cell surface receptors activates a variety of biochemical pathways. The role of each of these biochemical processes in transducing the mitogenic signal has yet to be clearly delineated. One biochemical pathway implicated in modulating the EGF response is linoleic acid metabolism. Our laboratory has report that specific lipoxygenase-derived metabolites of linoleic acid regulate growth factor signal transduction in fibroblasts. We now wish to examine whether linoleic acid metabolism can also play a role in the uncontrolled proliferation characteristic of neoplastic cells. We have transformed normal fibroblasts with either v- erbB oncogene or its cellular homolog, c-erbB2. The erbB oncogene of avian erythroblastosis retrovirus encodes a truncated EGF receptor and transforms cells via functioning as an activated growth receptor. We propose to study the effects of erbB oncogene expression on linoleic acid metabolism, and to compare these responses to the normal EGF-stimulated activity. The studies include characterizing the linoleic metabolites found in transformed cells, testing specific metabolites for their ability to modulate oncogene signal transduction, and examining the effects of blocking linoleic acid metabolism on altering the transformation process. These investigations should provide important information regarding the underlying mechanisms of normal growth control and neoplasia.
