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Modulation of Epidermal Growth Factor Receptor Gene Expression by Transforming Growth Factor-ß in a Human Breast Carcinoma Cell Line¹

Laboratory of Molecular Oncology, Veterans Administration Medical Center [J. A. F-P., D. J. K., P. D. H., V. D. T.], St. Louis, Missouri 63106; and Department of Medicine, St. Louis University [J. A. F-P., V. D. T.], St. Louis, Missouri 63104

Modulation of epidermal growth factor (EGF) receptor expression determines cellular responsiveness to EGF and might play an important role in growth inhibition. We have investigated the actions of EGF and/or transforming growth factor type ß (TGFß) on EGF receptor gene expression in MDA-468 human breast carcinoma cell line, which responds to EGF and/or TGFß with growth inhibition. Using the cDNA clone pE7, which encodes 2.4 kilobases of the human EGF receptor mRNA, as a hybridization probe, we have found that exposure of MDA-468 cells to EGF results in elevated levels of EGF receptor mRNA. This increase in mRNA accumulation showed time and dose dependence. Addition of TGFß enhances the accumulation of EGF receptor mRNA induced by EGF. Under this condition, stimulation could be detected after 1 h exposure to TGFß with a maximum at 6–8 h. A concentration of 10 pM TGFß gave detectable stimulation with maximal stimulation occurring at 300 pM in the presence of EGF (50 ng/ml). In contrast, TGFß alone had no significant effect on EGF receptor mRNA accumulation. In the presence of cycloheximide, the EGF receptor mRNA was superinduced in response to EGF. Treatment of the cells with TGFß enhances the EGF-dependent superinduction of EGF receptor mRNA produced by cycloheximide, suggesting that the stimulatory action of TGFß does not depend on continuous protein synthesis. The results described here are consistent with the hypothesis that the growth inhibitory action of TGFß in MDA-468 cells may be mediated, at least in part, by modulation of EGF receptor gene expression.

¹ This study was supported by VA Medical Research Funds, Project No. 001.

² To whom requests for reprints should be addressed, at Nuclear Medicine Service (115JC), VA Medical Center, 915 North Grand Boulevard, St. Louis, MO 63106.

Received 3/ 4/87. Revised 5/21/87. Accepted 5/27/87.