Oestrogen 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 p185erbB-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 p185erbB-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 p185erbB-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 it was enhanced by EGF. EGF stimulated both tyrosine phosphorylation and autokinase activity of p185erbB-2 down-regulates p185erbB-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.
Antoniotti
S
S
Department of Animal Biology, University of Torino, Italy.
Taverna
D
D
Maggiora
P
P
Sapei
M L
ML
Hynes
N E
NE
De Bortoli
M
M
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018734:Genes, erbB-2; D006801:Humans; D066298:In Vitro Techniques; D019000:Phosphotyrosine; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D004815:Epidermal Growth Factor; D004958:Estradiol; D019000:Phosphotyrosine; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine