Pedersen Nina Marie, Breen Kamilla, Rødland Marianne Skeie, Haslekås Camilla, Stang Espen, Madshus Inger Helene
Institute of Pathology, Faculty of Medicine, University of Oslo, Oslo, Norway.
Mol Cancer Res. 2009 Feb;7(2):275-84. doi: 10.1158/1541-7786.MCR-07-2183. Epub 2009 Feb 10.
Overexpression of the epidermal growth factor receptor (EGFR), ErbB2, and ErbB3 promotes growth and antiapoptotic signaling. Overexpression of ErbB2 in breast cancer is associated with poor clinical outcome, and ways of down-regulating ErbB2 are important as therapeutic approaches. In contrast to EGFR, ErbB2 has been shown to be endocytosis deficient. However, down-regulation of ErbB2 can be induced by incubation of cells with geldanamycin and geldanamycin derivatives, counteracting the stabilizing function of heat shock protein 90 on ErbB2. In the present study, we have made use of stably transfected isogenic cell lines expressing ErbB2 only or ErbB2 together with EGFR and/or ErbB3. We now show that whereas ErbB2 can be down-regulated by incubation with geldanamycin in cells expressing ErbB2 only, the rate of geldanamycin-induced down-regulation increases significantly when the cells additionally express EGFR and/or ErbB3. This increase does, however, not correlate with activation/phosphorylation of ErbB2. The potential of heterodimer formation in ErbB2-positive breast cancer cells could thus turn out to be prognostically predictive with respect to outcome of treatment with geldanamycin derivatives.
表皮生长因子受体（EGFR）、ErbB2和ErbB3的过表达促进生长和抗凋亡信号传导。乳腺癌中ErbB2的过表达与不良临床预后相关，下调ErbB2的方法作为治疗手段具有重要意义。与EGFR不同，ErbB2已被证明存在内吞缺陷。然而，用格尔德霉素及其衍生物处理细胞可诱导ErbB2下调，从而抵消热休克蛋白90对ErbB2的稳定作用。在本研究中，我们利用了稳定转染的同基因细胞系，这些细胞系仅表达ErbB2，或同时表达ErbB2与EGFR和/或ErbB3。我们现在表明，在仅表达ErbB2的细胞中，用格尔德霉素处理可使ErbB2下调，而当细胞额外表达EGFR和/或ErbB3时，格尔德霉素诱导的下调速率显著增加。然而，这种增加与ErbB2的激活/磷酸化无关。因此，ErbB2阳性乳腺癌细胞中异二聚体形成的可能性可能对格尔德霉素衍生物治疗的预后具有预测价值。
