Estrogen receptor-α directly regulates sensitivity to paclitaxel in neoadjuvant chemotherapy for breast cancer
Estrogen receptor-α directly regulates sensitivity to paclitaxel in neoadjuvant chemotherapy for breast cancer
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DOI：
10.1007/s10549-011-1758-x
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发表时间：
2012-06-01
影响因子：
3.8
通讯作者：
Yamaguchi, Yuri
中科院分区：
文献类型：
--
作者：
Tokuda, Emi;Seino, Yuko;Yamaguchi, Yuri
新辅助化疗（NAC）已成为晚期乳腺癌的标准治疗方法。一些预后指标，包括雌激素受体α (ER α)，被用来预测对NAC的反应。然而，ER α表达在化疗疗效中的分子意义尚不完全清楚。为了研究这一问题，我们首先使用雌激素反应元件-绿色荧光蛋白（ERE-GFP）作为报告基因，评估了nac前标本来源的乳腺癌细胞中ER α的转录活性，发现在未检测到或低表达GFP确定ER α活性的情况下，即使表达ER α蛋白也可以实现pCR（病理完全反应）。接下来，我们通过在ER阴性的SKBR3细胞中稳定表达ER α和在ER阳性的MCF-7细胞中通过sirna介导下调ER α，研究了ER α表达水平的改变对NAC关键药物紫杉醇敏感性的影响，结果表明ER α表达与紫杉醇敏感性呈负相关。我们还建立了抗紫杉醇MCF-7细胞克隆，发现它们比亲本细胞具有更高的雌激素诱导内质网活性。紫杉醇是一种微管稳定剂，而HDAC6（组蛋白去乙酰化酶6），我们之前确定为雌激素调节基因，通过α -微管蛋白的去乙酰化来破坏微管的稳定，从而增强细胞活力。最后，我们在此证明，在MCF-7细胞中ER α敲低可阻止α -微管蛋白的去乙酰化，从而增加对紫杉醇的敏感性。综上所述，这些结果表明，ER α表达通过对微管稳定性的影响，直接调节乳腺癌NAC对紫杉醇的敏感性。
Neoadjuvant chemotherapy (NAC) has become the standard treatment for advanced breast cancer. Several prognostic markers, including estrogen receptor-alpha (ER alpha), are used to predict the response to NAC. However, the molecular significance of ER alpha expression in the efficacy of chemotherapy is not yet fully understood. To examine this issue, we first evaluated ER alpha transcriptional activity in breast cancer cells derived from pre-NAC specimens using estrogen response element-green fluorescent protein (ERE-GFP) as a reporter gene, and found that, in the cases for which ER alpha activities determined by GFP expression were not detected or low, pCR (pathological complete response) could be achieved even though ER alpha protein was expressed. Next, we examined the effects of alterations in ER alpha expression levels on sensitivity to paclitaxel, a key drug in NAC, by stable expression of ER alpha in ER-negative SKBR3 cells and by siRNA-mediated down-regulation of ER alpha in ER-positive MCF-7 cells, and showed that ER alpha expression and sensitivity to paclitaxel showed an inverse correlation. We also established paclitaxel-resistant MCF-7 cell clones and found that they have higher estrogen-induced ER activity than parent cells. Paclitaxel is a microtubule-stabilizing agent, while HDAC6 (histone deacetylase 6), which we previously identified as an estrogen-regulated gene, enhances cell motility by destabilizing microtubules via deacetylation of alpha-tubulin. Finally, we demonstrate herein that ER alpha knockdown in MCF-7 cells prevents deacetylation of alpha-tubulin, thereby increasing sensitivity to paclitaxel. Taken together, these results suggest that ER alpha expression directly regulates sensitivity to paclitaxel in NAC for breast cancer via the effect on microtubule stability.