Rouzier Roman, Rajan Radhika, Wagner Peter, Hess Kenneth R, Gold David L, Stec James, Ayers Mark, Ross Jeffrey S, Zhang Peter, Buchholz Thomas A, Kuerer Henry, Green Marjorie, Arun Banu, Hortobagyi Gabriel N, Symmans W Fraser, Pusztai Lajos
Department of Breast Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8315-20. doi: 10.1073/pnas.0408974102. Epub 2005 May 24.
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 tau-negative 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.
乳腺癌对紫杉醇的敏感性存在差异。目前尚无诊断测试可识别对该药物敏感的肿瘤。我们使用U133A芯片来鉴定与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是差异表达最显著的基因。达到pCR的肿瘤mRNA表达显著更低（P < 0.3×10⁻⁵）。来自122例独立但治疗方式相似的患者的组织芯片用于免疫组化验证。74%的pCR病例tau蛋白呈阴性；pCR的优势比为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的独立预测因素。进行了小干扰RNA实验以检查tau的下调是否会在体外增加对化疗的敏感性。tau下调增加了乳腺癌细胞对紫杉醇的敏感性，但对表柔比星不敏感。使用微管蛋白聚合试验来评估tau是否调节紫杉醇与微管蛋白的结合。微管蛋白与tau预孵育导致紫杉醇结合减少以及紫杉醇诱导的微管聚合降低。这些数据表明低tau表达使微管对紫杉醇更敏感，并使乳腺癌细胞对该药物超敏感。低tau表达可作为选择紫杉醇治疗患者的标志物。抑制tau功能可能被用作增加对紫杉醇敏感性的治疗策略。
