Experiments are being conducted to determine the distribution and role of transforming growth factor alpha (TGFa ) in normal and malignant rodent and human mammary epithelial cells. Primary dimethylbenz (alpha) anthracene (DMBA) and nitrosomethylurea (NMU) induced rat mammary adenocarcinomas possess immunoreactive and biologically TGFalpha. A specific 4.8 Kb TGFalpha mRNA species could be detected in the DMBA - and NMU - induced rat mammary tumors. Ovariectomy produced a five to tenfold decrease in the expression of TGFa mRNA in the DMBA tumors. Nog 8 mouse mammary epithelial cells transfected with a plasmid containing a gluco- corticoid inducible MMTv-LTR linked to the point-mutated c-HA-ras proto-oncogene become transformed following the addition of dexamethesone (dex) to these cells. Following dex treatment, there is a rapid induction of the p21ras protein and of c-Ha-ras mRNA within 3 to 5 hours. During this interval there is a co- ordinate increase in the level of expression of TGFn mRNA and a subsequent increase in the production of TGFalpha protein. Human breast cancer cell lines are also producing TGFalpha and possess TGFalpha mRNA. In MCF-7 cells, the level of production of TGF alpha and TGF alpha mRNA expression can be enhanced by estrogens. Treatment of MCF-7 cells with a polyclonal anti-human TGF alpha antibody or with a monoclonal antibody against the human EGF receptor will inhibit the growth of these cells in vitro. Elevated levels of TGF alpha and TGF alpha mRNA can be detected in approximately 65% of primary human breast tumors. These results suggest that TGF alpha may function as an autocrine growth factor for a subset of rodent and human mammary tumor cells and that estrogens or activation or over- expression of a ras protooncogene may control the production of this growth factor.
