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Neu differentiation factor induces ErbB2 down-regulation and apoptosis of ErbB2-overexpressing breast tumor cells
J M Daly1, C B Jannot, R R Beerli
1Friedrich Miescher Institute, Basel, Switzerland.
Abstract:
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.
Insights
Neu differentiation factor (NDF) inhibits growth of ErbB2-overexpressing tumor cells by forming specific heterodimers with NDF receptors, leading to apoptosis. This contrasts with EGF receptor agonists, which do not inhibit growth.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Neu differentiation factor (NDF) is an epidermal growth factor (EGF)-related peptide that activates ErbB2 through heterodimerization with ErbB3 or ErbB4.
- EGF receptor (EGFR) agonists also induce heterodimers of EGFR and ErbB2, suggesting potential overlapping signaling pathways.
Purpose of the Study:
- To investigate the effect of NDF and EGFR agonists on the growth of ErbB2-overexpressing tumor cells.
- To determine whether heterodimerization with NDF receptors or EGFR influences growth inhibition and ErbB2 signaling.
Main Methods:
- Treatment of various breast and ovarian tumor cell lines with NDF and EGFR agonists (EGF, beta-cellulin, heparin-binding EGF).
- Assessment of cell growth inhibition, receptor expression levels, and cell cycle progression (G2-M arrest).
- Analysis of apoptosis induction following NDF treatment.
Main Results:
- NDF significantly inhibited the growth of ErbB2-overexpressing breast tumor cells (SKBR3, AU565, MDA-MB453) that also express NDF receptors.
- Cells with elevated ErbB2 but low NDF receptors, or low ErbB2 levels, were not growth inhibited by NDF.
- EGFR agonists did not inhibit the growth of ErbB2-overexpressing cells.
- NDF treatment led to G2-M arrest and induced apoptosis in SKBR3 cells, accompanied by ErbB2 down-regulation.
Conclusions:
- Formation of an ErbB2/NDF receptor heterodimer, but not an ErbB2/EGFR heterodimer, is crucial for NDF-mediated tumor cell growth inhibition.
- NDF induces apoptosis in tumor cells overexpressing ErbB2, representing a novel therapeutic mechanism.