Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
Cancer Res. 2011 Apr 1;71(7):2728-38. doi: 10.1158/0008-5472.CAN-10-2711. Epub 2011 Feb 24.
Taxol (paclitaxel) resistance represents a major challenge in breast cancer treatment. The TAZ (transcriptional co-activator with PDZ-binding motif) oncogene is a major component of the novel Hippo-LATS signaling pathway and a transcriptional coactivator that interacts with and activates multiple transcription factors to regulate various biological processes. Here, we report that elevated levels of TAZ found in human breast cancer cells are responsible for their resistance to Taxol. DNA microarray analysis identified the oncogenes Cyr61 and CTGF as downstream transcriptional targets of TAZ. Short hairpin RNA-mediated knockdown of both Cyr61 and CTGF reversed TAZ-induced Taxol resistance in breast cancer cells. Interaction of TAZ with the TEAD family of transcription factors was essential for TAZ to activate the Cyr61/CTGF promoters and to induce Taxol resistance. Our findings define the TAZ-TEAD-Cyr61/CTGF signaling pathway as an important modifier of the Taxol response in breast cancer cells, as well as highlighting it as a novel therapeutic target to treat drug-resistant breast cancers that arise commonly at advanced stages of disease.
紫杉醇耐药性是乳腺癌治疗的主要挑战。TAZ（含 PDZ 结合基序的转录共激活因子）癌基因是新的 Hippo-LATS 信号通路的主要组成部分，也是一种转录共激活因子，可与并激活多种转录因子，从而调节各种生物过程。在这里，我们报告称，在人类乳腺癌细胞中发现的高水平 TAZ 导致其对紫杉醇产生耐药性。DNA 微阵列分析鉴定出癌基因 Cyr61 和 CTGF 是 TAZ 的下游转录靶标。短发夹 RNA 介导的 Cyr61 和 CTGF 敲低可逆转 TAZ 诱导的乳腺癌细胞紫杉醇耐药性。TAZ 与 TEAD 转录因子家族的相互作用对于 TAZ 激活 Cyr61/CTGF 启动子并诱导紫杉醇耐药性至关重要。我们的研究结果将 TAZ-TEAD-Cyr61/CTGF 信号通路定义为乳腺癌细胞中紫杉醇反应的重要调节剂，并强调其作为治疗在疾病晚期常见的耐药性乳腺癌的新型治疗靶标。
