Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells
Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells
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DOI：
10.1016/j.bbrc.2003.12.007
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发表时间：
2004-01-16
影响因子：
3.1
通讯作者：
Pollak, M
中科院分区：
文献类型：
--
作者：
Lu, YH;Zi, XL;Pollak, M
三分之一的人乳腺癌中ErbB 2受体的过表达有助于上皮细胞的转化，并预测乳腺癌患者的预后不良。我们报道ErbB 2的过表达抑制IGF-I诱导的MAPK信号传导。与对照MCF-7/neo细胞相比，ErbB 2过表达MCF-7/HER 2 -18细胞中IGF-I诱导的MAPK磷酸化和MAPK激酶活性降低。在SKBR 3/IGF-IR细胞中，通过反义方法减少ErbB 2恢复IGF-I诱导的MAPK活化。在ErbB 2过表达的乳腺癌细胞中，IGF-I诱导的MAP激酶活化的抑制与IGF-I诱导的She酪氨酸磷酸化的降低相关，导致Grb 2与Shc的相关性降低和Raf磷酸化降低。然而，IGF-I诱导的IGF-I受体酪氨酸磷酸化和IRS-I和AKT磷酸化不受ErbB 2过表达的影响。与这些结果一致，我们观察到MAPK抑制剂PD 98059阻断的IGF-I刺激的增殖比例从MCF-7/neo细胞的82.6%下降到MCF-7/HER 2 -18细胞的41.2%。这些数据为IGF-IR和ErbB 2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的减弱依赖于IGF-I诱导的PI 3 K信号传导而不是IGF-I诱导的MAPK信号传导的观点一致。(C)2003年爱思唯尔公司All rights reserved.
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 She tyro sine-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. (C) 2003 Elsevier Inc. All rights reserved.