Estrogen receptor α mediates breast cancer cell resistance to paclitaxel through inhibition of apoptotic cell death
Estrogen receptor α mediates breast cancer cell resistance to paclitaxel through inhibition of apoptotic cell death
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DOI：
10.1158/0008-5472.can-06-4582
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发表时间：
2007-06-01
期刊：
影响因子：
11.2
通讯作者：
Fan, Weimin
中科院分区：
文献类型：
--
作者：
Sui, Meihua;Huang, Yi;Fan, Weimin
雌激素受体（ER）在65%的人类乳腺癌中表达。临床试验和回顾性分析的累积数据表明，某些化疗药物对ER阳性（ER+）肿瘤患者的疗效可能低于ER阴性（ER-）肿瘤患者。紫杉醇是一种用于乳腺癌化疗的活性药物。为了研究ER对紫杉醇治疗效果的可能影响及其潜在机制，我们通过将ER α表达载体稳定转染到ER-乳腺癌BCap 37细胞中建立了几种等基因ER+细胞系。我们发现，17-β雌二醇显著降低了紫杉醇在表达BCap 37的ER α中的总体细胞毒性，但对ER亲代细胞没有影响。进一步的分析表明，ER α在BCap 37细胞中的表达主要干扰紫杉醇诱导的凋亡性细胞死亡，而不影响紫杉醇诱导的微管集束和有丝分裂阻滞。此外，我们发现添加ICI 182，780（氟维司群）（一种选择性ER下调剂）可以完全逆转ER+ BCap 37细胞对紫杉醇的抗性。这些结果表明，ER α介导的乳腺肿瘤细胞对紫杉醇的耐药性是通过选择性抑制紫杉醇诱导的肿瘤细胞凋亡。此外，ICI 182，780的组合还使MCF-7和T47 D细胞系对紫杉醇的治疗敏感，这进一步证实了ER α与ER+肿瘤细胞中的耐药性之间的相关性。本研究的结果为了解ER介导的紫杉醇耐药和其他可能的抗肿瘤药物耐药提供了有用的信息。
Estrogen receptors (ER) are expressed in similar to 65% of human breast cancer. Cumulative data from clinical trials and retrospective analyses suggest that some chemotherapeutic agents may be less effective in patients with ER-positive (ER+) tumors than those with ER-negative (ER-) tumors. Paclitaxel is an active agent used in breast cancer chemotherapy. To investigate the possible influence of ER on the therapeutic efficacy of paclitaxel and its underlying mechanism, we established several isogenic ER+ cell lines by stable transfection of ER alpha expression vectors into ER- breast cancer BCap37 cells. We showed that 17-beta estradiol significantly reduces the overall cytotoxicity of paclitaxel in BCap37-expressing ER alpha but has no influence on the ER- parental cells. Further analyses indicate that expression of ER alpha in BCap37 cells mainly interferes with paclitaxel-induced apoptotic cell death, without affecting paclitaxel-induced microtubule bundling and mitotic arrest. Moreover, we found that the addition of ICI 182,780 (Fulvestrant), a selective ER down-regulator, could completely reverse the resistance of ER+ BCap37 cells to paclitaxel. These findings showed that ER alpha-mediated breast tumor cell resistance to paclitaxel was through selective inhibition of paclitaxel-induced tumor cell apoptosis. Additionally, the combination of ICI 182,780 also sensitizes MCF-7 and T47D cell lines to the treatment of paclitaxel, which further confirmed the correlation between ER alpha, and drug resistance in ER+ tumor cells. The results obtained from this study provide useful information for understanding ER-mediated resistance to paclitaxel and possibly other antineoplastic agents.