Autocrine interaction between TGFα and the EGF-receptor: quantitative requirements for induction of the malignant phenotype

Alterations affecting the epidermal growth factor (EGF)/transforming growth factor α (TGFα)-responsive mitogenic pathway are frequently detected in malignancies. In particular, the EGF-receptor (EGFR) molecule has been found overexpressed in a number of human tumors, and TGFα is produced by a large array of tumor cells. Gene transfer experiments have previously demonstrated that expression of either TGFα or EGFR alone is not sufficient to induce the transformed phenotype in NIH3T3 cells. In this study we sought to investigate the biological effect of expression of TGFα and high levels of EGFR in this model system. We demonstrate that the gene for TGFα acts as a potent oncogene in NIH3T3 cells overexpressing EGFR (NIH-EGFR, > 10⁶ EGFR). We further show that TGFα directly stimulates proliferation of the cell in which it is produced and provide evidence that the extracellular compartment of the transformed cell is the major site of interaction between TGFα and EGFR. Analysis of human tumor cell lines revealed a strong correlation between expression of TGFα and overexpression of EGFR. Moreover, high levels of EGF-independent tyrosine phosphorylation of the EGFR were detected both in NIH-EGFR expressing TGFα and in high EGFR and TGFα coexpressing human tumor cell lines. Thus, the two events instituting the EGFR/TGFα autocrine loop responsible for transformation in vitro may play a role in the development of some human malignancies.