Interferon-Induced Enhancement of Transforming Growth Factor-α Expression in a Human Breast Cancer Cell Line

Abstract

Previous work from our laboratory has demonstrated that γ-interferon (IFN) inhibits growth of the human breast carcinoma cell line MDA 468, while enhancing expression of epidermal growth factor receptor (EGFR). Epidermal growth factor at high levels is known to inhibit growth of this cell line. Because MDA 468 cells produce low levels of transforming growth factor (TGF)-α (a ligand for epidermal growth factor receptor), we reasoned that IFN-induced cytotoxicity could be partially mediated by enhanced secretion of TGF-α. Therefore, we determined the ability of IFN to modulate the endogenous expression of TGF-α by MDA 468 cells. IFN-γ, at 500 units/ml, increased the levels of TGF-α in serum-free conditioned media of MDA 468 cells 3-fold as measured by radioimmunoassay. TGF-α mRNA was similarly increased approximately 3-fold after 5 days of IFN treatment as determined by dot blot and Northern analysis. IFN increased expression of TGF-α in conditioned media in a dose-dependent fashion. Increased secretion of TGF-α into conditioned media was not observed at Days 1 and 3. Similarly, increases in TGF-α mRNA were not observed at those time points. These results demonstrate that IFN-γ enhanced secretion of TGF-α by MDA 468 cells. Although exogenous TGF-α inhibited MDA 468 cell growth, the role that the enhanced endogenous production of TGF-α plays in the cessation of cell growth induced by IFN remains to be determined.