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 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.
Daly
J M
JM
Friedrich Miescher Institute, Basel, Switzerland.
Jannot
C B
CB
Beerli
R R
RR
Graus-Porta
D
D
Maurer
F G
FG
Hynes
N E
NE
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists* / Q000378:metabolism; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D018734:Genes, erbB-2 / Q000187:drug effects*; D006023:Glycoproteins / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006023:Glycoproteins; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases; C587883:HBEGF protein, human