Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer
Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer
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DOI：
10.1158/1535-7163.mct-09-0140
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发表时间：
2009-06-01
影响因子：
5.7
通讯作者：
Wu, Wen Jin
中科院分区：
文献类型：
--
作者：
Dokmanovic, Milos;Hirsch, Dianne S.;Wu, Wen Jin
尽管曲妥珠单抗治疗改善了ErbB2阳性乳腺癌妇女的预后，但许多对曲妥珠单抗有初步反应的患者随后在一年内获得耐药性。Ras样小GTP酶rac1参与了细胞生长和形态的调控，并被认为与乳腺癌的进展和转移有关。在这里，我们表明，当亲本SKBR3细胞对曲妥珠单抗产生抗药性时，rac1活性增加，导致细胞形态改变，并伴随着显著的细胞骨架解体。此外，在曲妥珠单抗耐药的SKBR3细胞中，曲妥珠单抗介导的ErbB2下调和表皮生长因子诱导的表皮生长因子受体下调均受到损害，表明耐药细胞中ErbB受体的内源性下调受到了损害。这导致ErbB2在细胞表面异常积聚，并在曲妥珠单抗耐药的SKBR3细胞中增强ErbB2和细胞外信号调节激酶的活性。此外，在亲本SKBR3细胞中过表达具有结构性活性的rac1G12V会降低对曲妥珠单抗的敏感性。曲妥珠单抗耐药的SKBR3细胞被特异性的rac1抑制剂NSC23766抑制后，表现出与亲本SKBR3细胞相似的细胞形态。此外，我们发现在耐药的SKBR3细胞中，NSC23766恢复了曲妥珠单抗介导的ErbB2的胞内下调，并降低了细胞外信号调节激酶的活性。我们的发现强调了rac1在人乳腺癌细胞对曲妥珠单抗耐药中的重要作用，并发现曲妥珠单抗介导的细胞内ErbB2下调是曲妥珠单抗耐药的新机制。NSC23766对曲妥珠单抗耐药的SKBR3细胞的显著作用值得进一步研究NSC23766作为曲妥珠单抗耐药乳腺癌的潜在治疗药物。[摩尔癌症治疗2009；8(6)：1557-69]
Although treatment with trastuzumab improves outcomes for women with ErbB2-positive breast cancer, many patients who achieve an initial response to trastuzumab subsequently acquire resistance within 1 year. Rac1, a Ras-like small GTPase, has been implicated in the control of cell growth and morphology and is believed to be associated with breast cancer progression and metastasis. Here, we show that when parental SKBR3 cells become resistant to trastuzumab, Rac1 activity is increased, leading to altered cell morphology, which is accompanied by significant cytoskeleton disorganization. Furthermore, both trastuzumab-mediated down-regulation of ErbB2 and epidermal growth factor-induced down-regulation of epidermal growth factor receptor are impaired in the trastuzumab-resistant SKBR3 cells, indicating that the endocytic down-regulation of ErbB receptors is compromised in the resistant cells. This results in an aberrant accumulation of ErbB2 on the cell surface and enhanced ErbB2 and extracellular signal-regulated kinase activity in trastuzumab-resistant SKBR3 cells. Additionally, overexpression of constitutively active Rac1G12V in parental SKBR3 cells reduces sensitivity to trastuzumab. After reduction of Rac1 activity by NSC23766, a specific Rac1 inhibitor, trastuzumab-resistant SKBR3 cells display a cellular morphology similar to parental SKBR3 cells. Moreover, we show that NSC23766 restores trastuzumab-mediated endocytic down-regulation of ErbB2 and reduces extracellular signal regulated kinase activity in resistant SKBR3 cells. Our findings highlight an important role for Rac1 in trastuzumab resistance of human breast cancer cells and identify the impaired trastuzumab-mediated endocytic down-regulation of ErbB2 as a novel mechanism of trastuzumab resistance. The significant effects of NSC23766 on trastuzumab-resistant SKBR3 cells warrant further study of NSC23766 as a potential treatment of trastuzumab-resistant breast cancers. [Mol Cancer Ther 2009;8(6):1557-69]