Turton N J, Judah D J, Riley J, Davies R, Lipson D, Styles J A, Smith A G, Gant T W
MRC Toxicology Unit, University of Leicester, Lancaster Road, Leicester, LE1 9HN UK.
Oncogene. 2001 Mar 15;20(11):1300-6. doi: 10.1038/sj.onc.1204235.
The multidrug resistance (MDR) phenotype is a major cause of cancer treatment failure. Here the expressions of 4224 genes were analysed for association with intrinsic or acquired doxorubicin (DOX) resistance. A cluster of overexpressed genes related to DOX resistance was observed. Included in this cluster was ABCB1 the P-glycoprotein transporter protein gene and MMP1 (Matrix Metalloproteinase 1), indicative of the invasive nature of resistant cells, and the oxytocin receptor (OXTR), a potential new therapeutic target. Overexpression of genes associated with xenobiotic transformation, cell transformation, cell signalling and lymphocyte activation was also associated with DOX resistance as was estrogen receptor negativity. In all carcinoma cells, compared with HBL100 a putatively normal breast epithelial cell line, a cluster of overexpressed genes was identified which included several keratins, in particular keratins 8 and 18 which are regulated through the ras signalling pathway. Analysis of genomic amplifications and deletions revealed specific genetic alterations common to both intrinsic and acquired DOX resistance including ABCB1, PGY3 (ABCB4) and BAK. The findings shown here indicate new possibilities for the diagnosis of DOX resistance using gene expression, and potential novel therapeutic targets for pharmacological intervention.
多药耐药（MDR）表型是癌症治疗失败的主要原因。在此，分析了4224个基因的表达与阿霉素（DOX）固有耐药性或获得性耐药性的相关性。观察到一组与DOX耐药相关的过表达基因。该组基因包括P-糖蛋白转运蛋白基因ABCB1和基质金属蛋白酶1（MMP1），这表明耐药细胞具有侵袭性，还包括催产素受体（OXTR），它是一个潜在的新治疗靶点。与异生物质转化、细胞转化、细胞信号传导和淋巴细胞激活相关的基因过表达也与DOX耐药相关，雌激素受体阴性也是如此。在所有癌细胞中，与假定正常的乳腺上皮细胞系HBL100相比，鉴定出一组过表达基因，其中包括几种角蛋白，特别是通过ras信号通路调控的角蛋白8和18。基因组扩增和缺失分析揭示了DOX固有耐药性和获得性耐药性共有的特定基因改变，包括ABCB1、PGY3（ABCB4）和BAK。此处所示的研究结果表明利用基因表达诊断DOX耐药性有新的可能性，以及药物干预潜在的新治疗靶点。
