ALPHA TRANSFORMING GROWTH FACTORS IN RODENT AND HUMAN MAMMARY CARCINOMAS

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Experiments are being conducted to determine the distribution and role of alpha transforming growth factors (alpha TGFs) in normal and malignant rodent and human mammary epithelial cells. Primary dimethylbenz (alpha) anthracene (DMBA) and nitrosomethylurea (NMU) rat mammary adenocarcinomas possess three to seven-fold more biologically active and immunoreactive alpha TGFs than transplantable DMBA-I and NMU-II carcinomas. Moreover, a specific 5.0 kb mRNA species could be detected in the primary DMBA and NMU tumors following hybridization of poly A(+) RNA to a human and mouse alpha TGF cDNA probes but not in the DMBA-I or NMU-II tumors. Ovariectomy produced a two to three-fold decrease in the level of alpha TGFs in the primary DMBA tumors which was preceeded by a loss in the expression of alpha TGF mRNA. Mouse mammary epithelial which have been transformed with a point-mutated c-Ha-ras proto-oncogene, NMuMG/rasH cells, become resistant to the growth promoting effects of EGF because these cells have an increased capacity to synthesize alpha TGF mRNA. Human breast cancer cell lines are also producing alpha TGF and possess alpha TGF mRNA. In MCF-7 cells, the level of production of alpha TGF and TGF alpha mRNA expression can be enhanced by estrogens and blocked by anti-estrogens. In addition 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 immunoreactive alpha TGF and alpha TGF mRNA can be detected in approximately 65% of primary human breast carcinomas. These is a strong positive correlation between the presence of alpha TGF mRNA and the presence of functional estrogen receptors in a subset of these tumors. These results suggest that TGF alpha may function as an autocrine growth factor for a subset of rodent and human mammary tumor cells which are estrogen responsive and that the activation or overexpression of a ras proto-oncogene may also control the level of TGF alpha production.