Targeting Bcl-2 in Herceptin-Resistant Breast Cancer Cell Lines.
Targeting Bcl-2 in Herceptin-Resistant Breast Cancer Cell Lines.
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DOI：
10.2174/187569211796957584
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发表时间：
2011-09
影响因子：
--
通讯作者：
Nahta R
中科院分区：
文献类型：
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作者：
Crawford A;Nahta R
对Herceptin的获得性耐药是治疗HER2过表达乳腺癌的主要临床问题。了解导致耐药的分子机制将有助于识别新的治疗靶点和治疗反应的预测因素。为此，抗凋亡蛋白的上调与HER2靶向药物拉帕替尼的耐药性有关，但尚未与Herceptin耐药性有关。目前这项研究的目的是确定在获得性赫赛汀耐药细胞中，Bcl-2抗凋亡蛋白是否是一个潜在的治疗靶点。本研究以高表达BT474 HER2的乳腺癌细胞株和BT474获得的Herceptin抗性克隆为模型。用Western blotting检测bcl2和bax的表达。在没有或存在Herceptin的情况下，用Bcl2抑制剂ABT-737处理细胞，进行增殖分析。用Western blotting和建立的细胞增殖实验检测PI3K和IKK抑制对Bcl2表达和Herceptin敏感性的影响。我们发现对Herceptin具有获得性耐药的细胞有增加的Bcl2/Bax比率。耐药细胞对ABT-737的敏感性增加。此外，药物抑制Bcl2可提高获得性耐药细胞对Herceptin的敏感性。最后，PI3K和IKK的抑制下调了耐药细胞中Bcl2的表达，并增加了对Herceptin的敏感性。综上所述，这些新的观察结果支持了对Herceptin耐药乳腺癌进行Bcl2靶向治疗的进一步研究，重要的是，未来将研究Bcl2表达作为HER2过表达乳腺癌患者Herceptin反应的潜在预测因子。
Acquired resistance to Herceptin is a major clinical problem in the treatment of HER2-overexpressing breast cancer. Understanding the molecular mechanisms leading to resistance will allow identification of novel therapeutic targets and predictors of therapeutic response. To this end, up-regulation of anti-apoptotic proteins has been associated with resistance to the HER2-targeted drug lapatinib, but has not yet been linked to Herceptin resistance. The aim of the current study was to determine if the Bcl-2 anti-apoptotic protein is a potential therapeutic target in cells with acquired Herceptin resistance. The BT474 HER2-overexpressing breast cancer cell line and BT474-derived acquired Herceptin-resistant clones were used as models in this study. Bcl-2 and Bax expression were assessed by Western blotting. Proliferation assays were performed on cells treated with the Bcl-2 inhibitor ABT-737 in the absence or presence of Herceptin. Finally, the effect of PI3K inhibition or IKK inhibition on Bcl-2 expression and Herceptin sensitivity was examined by Western blotting and established proliferation assays. We show that cells with acquired resistance to Herceptin have an increased Bcl-2:Bax ratio. Resistant cells have increased sensitivity to ABT-737. Further, pharmacologic inhibition of Bcl-2 improved sensitivity to Herceptin in acquired resistant cells. Finally, PI3K and IKK inhibition down-regulated Bcl-2 expression and increased sensitivity to Herceptin in resistant cells. Taken together, these new observations support further study of Bcl-2-targeted therapies in Herceptin-resistant breast cancers, and importantly, future investigation of Bcl-2 expression as a potential predictor of Herceptin response in patients with HER2-overexpressing breast cancer.