ESTROGEN AND EPIDERMAL GROWTH-FACTOR DOWN-REGULATE ERBB-2 ONCOGENE PROTEIN EXPRESSION IN BREAST-CANCER CELLS BY DIFFERENT MECHANISMS

Mitogen-induced mammary cell growth is often accompanied by decreased levels of expression of the p185(erbB-2) protein. We have previously reported that oestrogen inhibits erbB-2 mRNA and protein expression in breast cancer cells, while epidermal growth factor (EGF) treatment has been shown to decrease p185(erbB-2) levels in normal mouse mammary epithelial cells. In the present work, we studied the effect of oestrogen and EGF on erbB-2 expression in oestrogen-responsive breast cancer cells. We observed that both oestrogen and EGF comparably down-regulated p185(erbB-2) levels, while stimulating growth of T47D and ZR75.1 cells. Oestrogens, but not EGF, concomitantly down-regulated erbB-2 mRNA. Run-on analysis showed a reduced erbB-2 transcription rate in the presence of oestrogens. Furthermore, the transcriptional activity of a 219 bp proximal fragment of the human erbB-2 promoter was repressed by oestrogens, whereas if was enhanced by EGF. EGF stimulated both tyrosine phosphorylation and autokinase activity of p185(erbB-2) We conclude that oestrogens, but not EGF, inhibit erbB-2 expression by transcriptional repression, while EGF down-regulates p185(erbB-2) at a post-translational level. Thus, two factors converging in terms of effects on cell growth, display divergent mechanisms of regulation of erbB-2 expression.