Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer
| العنوان: | 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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| المؤلفون: | Dianne S. Hirsch, Wen Jin Wu, Milos Dokmanovic, Yi Shen |
| المصدر: | Molecular Cancer Therapeutics. 8:1557-1569 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | rac1 GTP-Binding Protein, Cancer Research, Receptor, ErbB-2, Blotting, Western, Down-Regulation, Antineoplastic Agents, Breast Neoplasms, Antibodies, Monoclonal, Humanized, Cell morphology, Metastasis, Breast cancer, Trastuzumab, Cell Line, Tumor, medicine, Humans, Microscopy, Phase-Contrast, Mitogen-Activated Protein Kinase 8, Epidermal growth factor receptor, Kinase activity, skin and connective tissue diseases, neoplasms, Cytoskeleton, Cell Proliferation, Mitogen-Activated Protein Kinase 1, Microscopy, Confocal, Mitogen-Activated Protein Kinase 3, Dose-Response Relationship, Drug, biology, Cell growth, business.industry, Antibodies, Monoclonal, medicine.disease, Actins, Endocytosis, Pyrimidines, Oncology, Drug Resistance, Neoplasm, Mutation, Immunology, Cancer cell, Aminoquinolines, Cancer research, biology.protein, business, medicine.drug |
| الوصف: | 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] |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2d3394526ef71035f4bc7bf17904062d https://doi.org/10.1158/1535-7163.mct-09-0140 |
| رقم الأكسشن: | edsair.doi.dedup.....2d3394526ef71035f4bc7bf17904062d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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