Lu Yuhong, Zi Xiaolin, Zhao Yunhua, Pollak Michael
Division of Experimental Medicine, Department of Medicine and Department of Oncology, McGill University, Montreal, Que, Canada.
Biochem Biophys Res Commun. 2004 Jan 16;313(3):709-15. doi: 10.1016/j.bbrc.2003.12.007.
Overexpression of the ErbB2 receptor in one-third of human breast cancers contributes to the transformation of epithelial cells and predicts poor prognosis for breast cancer patients. We report that the overexpression of ErbB2 inhibits IGF-I-induced MAPK signaling. IGF-I-induced MAPK phosphorylation and MAPK kinase activity are reduced in ErbB2 overexpressing MCF-7/HER2-18 cells relative to control MCF-7/neo cells. In SKBR3/IGF-IR cells, reduction of ErbB2 by antisense methodology restores the IGF-I-induced MAPK activation. The inhibition of IGF-I-induced MAP kinase activation in ErbB2 overexpressing breast cancer cells is correlated with decreased IGF-I-induced Shc tyrosine-phosphorylation, leading to a decreased association of Grb2 with Shc and decreased Raf phosphorylation. However, IGF-I-induced tyrosine-phosphorylation of IGF-I receptor and IRS-I and AKT phosphorylation were unaffected by ErbB2 overexpression. Consistent with these results, we observed that the proportion of IGF-I-stimulated proliferation blocked by the MAPK inhibitor PD98059 fell from 82.6% in MCF-7/neo cells to 41.2% in MCF-7/HER2-18 cells. These data provide evidence for interplay between the IGF-IR and ErbB2 signaling pathways. They are consistent with the view that the IGF-IR mediated attenuation of trastuzumab-induced growth inhibition we recently described is dependent on IGF-I-induced PI3K signaling rather than IGF-I-induced MAPK signaling.
三分之一的人类乳腺癌中存在ErbB2受体过表达，这会促使上皮细胞发生转化，并预示着乳腺癌患者预后不良。我们报告称，ErbB2过表达会抑制IGF-I诱导的MAPK信号传导。与对照MCF-7/neo细胞相比，在过表达ErbB2的MCF-7/HER2-18细胞中，IGF-I诱导的MAPK磷酸化和MAPK激酶活性降低。在SKBR3/IGF-IR细胞中，采用反义方法降低ErbB2可恢复IGF-I诱导的MAPK激活。在过表达ErbB2的乳腺癌细胞中，IGF-I诱导的MAP激酶激活受到抑制，这与IGF-I诱导的Shc酪氨酸磷酸化减少相关，导致Grb2与Shc的结合减少以及Raf磷酸化减少。然而，IGF-I诱导的IGF-I受体和IRS-I的酪氨酸磷酸化以及AKT磷酸化不受ErbB2过表达的影响。与这些结果一致，我们观察到，MAPK抑制剂PD98059阻断的IGF-I刺激的增殖比例从MCF-7/neo细胞中的82.6%降至MCF-7/HER2-18细胞中的41.2%。这些数据为IGF-IR和ErbB2信号通路之间的相互作用提供了证据。它们与我们最近描述的IGF-IR介导的曲妥珠单抗诱导的生长抑制减弱依赖于IGF-I诱导的PI3K信号传导而非IGF-I诱导的MAPK信号传导这一观点一致。
