Daly J M, Jannot C B, Beerli R R, Graus-Porta D, Maurer F G, Hynes N E
Friedrich Miescher Institute, Basel, Switzerland.
Cancer Res. 1997 Sep 1;57(17):3804-11.
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.
神经分化因子（NDF）是表皮生长因子（EGF）相关肽家族的成员，它通过与NDF受体ErbB3和ErbB4异源二聚化来激活ErbB2。同样，表皮生长因子受体（EGFR）激动剂可诱导EGFR与ErbB2形成异源二聚体。在本文中，我们发现过表达ErbB2的乳腺癌细胞SKBR3、AU565和MDA - MB453受到NDF的生长抑制。ErbB2水平升高但NDF受体很少或没有的细胞（SKOV3和MDA - MB361），或ErbB2水平低的细胞（T47D和MCF7）没有生长抑制现象。所测试的EGFR激动剂（EGF、β - 细胞ulin或肝素结合型EGF）均未抑制过表达ErbB2细胞的生长。这些结果表明，形成ErbB2/NDF受体异源二聚体而非ErbB2/EGFR异源二聚体可促进生长抑制。此外，NDF导致ErbB2下调，但不影响ErbB3。我们在SKBR3细胞中进一步研究了这种抑制作用的潜在机制，该细胞受到NDF 95%的生长抑制。NDF处理24小时后可见G2 - M期阻滞，从第2天开始可检测到凋亡增加。这些结果首次证明NDF可诱导过表达ErbB2的肿瘤细胞凋亡。
