Microtubule-associated protein tau: A marker of paclitaxel sensitivity in breast cancer
Microtubule-associated protein tau: A marker of paclitaxel sensitivity in breast cancer
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DOI：
10.1073/pnas.0408974102
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发表时间：
2005-06-07
影响因子：
11.1
通讯作者：
Pusztai, L
中科院分区：
文献类型：
--
作者：
Rouzier, R;Rajan, R;Pusztai, L
乳腺癌对紫杉醇表现出不同的敏感性。没有诊断测试可以识别对该药物敏感的肿瘤。我们使用 U133A 芯片来识别与 I-III 期乳腺癌 (n = 82) 术前含紫杉醇化疗的病理完全缓解 (pCR) 相关的基因。 Tau 是表达差异最大的基因。 pCR 肿瘤的 mRNA 表达显着降低 (P < 0.3 x 10(-5))。来自 122 名独立但接受类似治疗的患者的组织阵列用于通过免疫组织化学进行验证。 74% 的 pCR 病例的 tau 蛋白呈阴性； PCR 的比值比为 3.7（95% 置信区间，1.6-8.6；P = 0.0013）。在多变量分析中，核分级 (P < 0.01)、年龄 < 50 岁 (P = 0.03) 和 tau 阴性状态 (P = 0.04) 是 pCR 的独立预测因子。进行小干扰 RNA 实验来检查 tau 的下调是否会增加体外化疗的敏感性。 tau 蛋白的下调会增加乳腺癌细胞对紫杉醇的敏感性，但不会增加对表柔比星的敏感性。微管蛋白聚合测定用于评估 tau 蛋白是否调节紫杉醇与微管蛋白的结合。微管蛋白与 tau 预孵育会导致紫杉醇结合减少并减少紫杉醇诱导的微管聚合。这些数据表明，低 tau 表达使微管更容易受到紫杉醇的影响，并使乳腺癌细胞对该药物过敏。低 tau 表达可用作选择接受紫杉醇治疗的患者的标志物。 tau 功能的抑制可能被用作增加对紫杉醇敏感性的治疗策略。
Breast cancers show variable sensitivity to paclitaxel. There is no diagnostic test to identify tumors that are sensitive to this drug. We used U133A chips to identify genes that are associated with pathologic complete response (pCR) to preoperative paclitaxel-containing chemotherapy in stage I-III breast cancer (n = 82). Tau was the most differentially expressed gene. Tumors with pCR had significantly lower (P < 0.3 x 10(-5)) mRNA expression. Tissue arrays from 122 independent but similarly treated patients were used for validation by immunohistochemistry. Seventy-four percent of pCR cases were tau protein negative; the odds ratio for pCR was 3.7 (95% confidence interval, 1.6-8.6; P = 0.0013). In multivariate analysis, nuclear grade (P < 0.01), age < 50 (P = 0.03), and taunegative status (P = 0.04) were independent predictors of pCR. Small interfering RNA experiments were performed to examine whether down-regulation of tau increases sensitivity to chemotherapy in vitro. Down-regulation of tau increased sensitivity of breast cancer cells to paclitaxel but not to epirubicin. Tubulin polymerization assay was used to assess whether tau modulates binding of paclitaxel to tubulin. Preincubation of tubulin with tau resulted in decreased paclitaxel binding and reduced paclitaxel-induced microtubule polymerization. These data suggest that low tau expression renders microtubules more vulnerable to paclitaxel and makes breast cancer cells hypersensitive to this drug. Low tau expression may be used as a marker to select patients for paclitaxel therapy. Inhibition of tau function might be exploited as a therapeutic strategy to increase sensitivity to paclitaxel.