Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, Taiwan.
J Biol Chem. 2010 Sep 17;285(38):29279-85. doi: 10.1074/jbc.C110.114124. Epub 2010 Jul 9.
Co-amplification and co-overexpression of ErbB2 and Grb7 are frequently found in various cancers, including breast cancer. Biochemical and functional correlations of the two molecules have identified Grb7 to be a pivotal mediator downstream of ErbB2-mediated oncogenesis. However, it remains largely unknown how Grb7 is involve in the ErbB2-mediated tumorigenesis. In this study, we show that Grb7-mediated cell proliferation and growth are essential for the tumorigenesis that occurs in ErbB2-Grb7-overexpressing breast cancer cells. Intrinsically, EGF-induced de novo Grb7 tyrosine phosphorylation/activation recruits and activates Ras-GTPases and subsequently promotes the phosphorylation of ERK1/2, thereby stimulating tumor growth. Furthermore, we also found the anti-tumor effect could be synergized by co-treatment with Herceptin plus Grb7 knockdown in Sk-Br3 breast cancer cells. Our findings illustrate an underlying mechanism by which Grb7 promotes tumorigenesis through the formation of a novel EGFR-Grb7-Ras signaling complex, thereby highlighting the potential strategy of targeting Grb7 as an anti-breast cancer therapy.
ErbB2 和 Grb7 的共扩增和共过表达在包括乳腺癌在内的各种癌症中经常被发现。这两种分子的生化和功能相关性已经确定 Grb7 是 ErbB2 介导的致癌作用的关键下游介质。然而，Grb7 如何参与 ErbB2 介导的肿瘤发生在很大程度上仍然未知。在这项研究中，我们表明 Grb7 介导的细胞增殖和生长对于在 ErbB2-Grb7 过表达的乳腺癌细胞中发生的肿瘤发生是必不可少的。本质上，EGF 诱导的新 Grb7 酪氨酸磷酸化/激活募集并激活 Ras-GTPases，并随后促进 ERK1/2 的磷酸化，从而刺激肿瘤生长。此外，我们还发现，在 Sk-Br3 乳腺癌细胞中，用赫赛汀加 Grb7 敲低联合治疗可以协同发挥抗肿瘤作用。我们的研究结果说明了 Grb7 通过形成一种新的 EGFR-Grb7-Ras 信号复合物来促进肿瘤发生的潜在机制，从而突出了将 Grb7 作为抗乳腺癌治疗的潜在策略。
