Lee Soo-Chin, Xu Xin, Lim Yi-Wan, Iau Philip, Sukri Norita, Lim Siew-Eng, Yap Hui Ling, Yeo Wee-Lee, Tan Patrick, Tan Sing-Huang, McLeod Howard, Goh Boon-Cher
Departments of aHaematology-Oncology bSurgery, National University Hospital cNational Cancer Centre, Singapore dUniversity of North Carolina, Chapel Hill, USA.
Pharmacogenet Genomics. 2009 Mar;19(3):181-92. doi: 10.1097/FPC.0b013e32831ebb5d.
Studying chemotherapy-induced gene expression changes in vivo, which could provide insights into mechanisms of chemotherapy resistance.
We analyzed and compared tumor gene expression changes of about 38 500 genes before and 3 weeks after doxorubicin or docetaxel treatment in 47 breast cancer patients.
By using the median expression level of each probe set as the parameter, less than 5% of genes were upregulated or downregulated by more than 50% after treatment with either drug. Doxorubicin and docetaxel concordantly induced 251 genes predominantly involved in protein and macromolecule metabolism (upregulated), and cell cycle and DNA/RNA metabolism (downregulated). Doxorubicin treatment resulted in coregulation of a cluster of 345 probe sets involved in focal adhesion, Jak-Stat signaling pathway, cell adhesion molecules, and natural killer cell mediated cytotoxicity, whereas docetaxel treatment resulted in coregulation of a cluster of 448 probe sets involved in focal adhesion, neurodegenerative disorders, sphingolipid metabolism, and cell cycle. Tumors that were intrinsically sensitive or resistant to doxorubicin or docetaxel evoked distinct gene expression changes in response to the drug; doxorubicin-resistant tumors upregulated genes that were enriched for ErbB signaling, ubiquitin-mediated proteolysis, TGF-beta signaling, and MAP-kinase signaling pathways, whereas docetaxel-resistant tumors upregulated genes that were enriched for focal adhesion and regulation of actin cytoskeleton. The drug-specific tumor gene expression changes were validated in independent in-vitro and in-vivo datasets.
Gene expression alterations of breast cancer were specific to doxorubicin and docetaxel treatment, and yielded mechanistic insights into resistance to either drug. Gene expression analysis provides more global perspectives on resistance pathways that could be exploited for therapeutic selection.
研究化疗在体内诱导的基因表达变化，这可为化疗耐药机制提供见解。
我们分析并比较了47例乳腺癌患者在多柔比星或多西他赛治疗前及治疗3周后约38500个基因的肿瘤基因表达变化。
以每个探针集的中位表达水平为参数，两种药物治疗后，上调或下调超过50%的基因不到5%。多柔比星和多西他赛一致诱导251个主要参与蛋白质和大分子代谢（上调）以及细胞周期和DNA/RNA代谢（下调）的基因。多柔比星治疗导致一组345个参与粘着斑、Jak-Stat信号通路、细胞粘附分子和自然杀伤细胞介导的细胞毒性的探针集共同调控，而多西他赛治疗导致一组448个参与粘着斑、神经退行性疾病、鞘脂代谢和细胞周期的探针集共同调控。对多柔比星或多西他赛内在敏感或耐药的肿瘤对药物产生不同的基因表达变化；多柔比星耐药肿瘤上调富含表皮生长因子受体（ErbB）信号、泛素介导的蛋白水解、转化生长因子-β（TGF-β）信号和丝裂原活化蛋白激酶（MAP）信号通路的基因，而多西他赛耐药肿瘤上调富含粘着斑和肌动蛋白细胞骨架调节的基因。药物特异性的肿瘤基因表达变化在独立的体外和体内数据集中得到验证。
乳腺癌的基因表达改变对多柔比星和多西他赛治疗具有特异性，并为对任一药物的耐药机制提供了见解。基因表达分析为可用于治疗选择的耐药途径提供了更全面的观点。
