Neu differentiation factor induces ErbB2 down-regulation and apoptosis of ErbB2-overexpressing breast tumor cells

Neu differentiation factor (NDF), a member of the epidermal growth factor (EGF)-related peptide family, activates ErbB2 via heterodimerization with the NDF receptors ErbB3 and ErbB4. In a similar fashion, EGF receptor (EGFR) agonists induce heterodimers of EGFR and ErbB2. In this paper, we show that...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1997-09, Vol.57 (17), p.3804-3811
Main Authors: DALY, J. M, JANNOT, C. B, BEERLI, R. R, GRAUS-PORTA, D, MAURER, F. G, HYNES, N. E
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Apoptosis - genetics
Biological and medical sciences
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Division - drug effects
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Down-Regulation
Epidermal Growth Factor - pharmacology
Female
Fundamental and applied biological sciences. Psychology
G2 Phase - drug effects
Genes, erbB-2 - drug effects
Glycoproteins - pharmacology
Heparin-binding EGF-like Growth Factor
Humans
Intercellular Signaling Peptides and Proteins
Molecular and cellular biology
Neuregulins
Receptor, Epidermal Growth Factor - agonists
Receptor, Epidermal Growth Factor - metabolism
Receptor, ErbB-2 - drug effects
Receptor, ErbB-2 - metabolism
Tumor Cells, Cultured - drug effects
Tumor Cells, Cultured - metabolism
Tumor Cells, Cultured - pathology
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Summary:Neu differentiation factor (NDF), a member of the epidermal growth factor (EGF)-related peptide family, activates ErbB2 via heterodimerization with the NDF receptors ErbB3 and ErbB4. In a similar fashion, EGF receptor (EGFR) agonists induce heterodimers of EGFR and ErbB2. In this paper, we show that the ErbB2-overexpressing breast tumor cells SKBR3, AU565, and MDA-MB453 are growth inhibited by NDF. Cells with elevated levels of ErbB2 but little or no NDF receptors (SKOV3 and MDA-MB361) or cells with low levels of ErbB2 (T47D and MCF7) are not growth inhibited. None of the EGFR agonists tested (EGF, beta-cellulin, or heparin-binding EGF) inhibited growth of ErbB2-overexpressing cells. These results suggest that formation of an ErbB2/NDF receptor heterodimer, but not of an ErbB2/EGFR heterodimer, promotes growth inhibition. In addition, NDF caused a down-regulation of ErbB2 but not of ErbB3. The mechanism underlying the inhibitory effect was examined further in SKBR3 cells, which are 95% growth inhibited by NDF. A G2-M arrest is seen 24 h after NDF treatment, and increased apoptosis is detectable from day 2 onward. The results demonstrate for the first time that NDF induces apoptosis of tumor cells overexpressing ErbB2.
ISSN:0008-5472
1538-7445