TGFalpha is produced as a biologically active, high molecular weight integral membrane glycoprotein that undergoes complex processing to its mature 5.6kd form. We have shown that TGFalpha is produced by normal and transformed epithelial cells. While its precise role in neoplasia is unknown, we have recently demonstrated that overproduction of TGFalpha targeted to the mammary gland in transgenic mice leads to mammary carcinoma. In this model, however, events in addition to overexpression of TGFalpha are required for the malignant phenotype. By use of polyclonal antibodies that we have generated to different regions of the proTGFalpha molecule, we propose to fully characterize its production and processing in representative normal and transformed epithelial cell and tissues. In addition, we propose to identify likely second events that accompany the malignant phenotype in the mouse mammary transgenic model. Finally in transgenic models in which TGFalpha is overexpressed in the colon, we propose to test the hypothesis that TGFalpha acts as a tumor promoter. These studies are likely to provide important new understanding into the role of TGFalpha in the development of two commonly encountered human malignancies, mammary and colonic neoplasia.
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