Joint Research Laboratory of the Hungarian Academy of Sciences and the Semmelweis University, Semmelweis University 1st Department of Pediatrics, Budapest, Hungary.
Br J Cancer. 2010 Jan 19;102(2):361-8. doi: 10.1038/sj.bjc.6605478. Epub 2009 Dec 15.
To date individual markers have failed to correctly predict resistance against anticancer agents in breast cancer. We used gene expression patterns attributable to chemotherapy-resistant cells to detect potential new biomarkers related to anthracycline resistance. One of the genes, PSMB7, was selected for further functional studies and clinical validation.
We contrasted the expression profiles of four pairs of different human tumour cell lines and of their counterparts resistant to doxorubicin. Observed overexpression of PSMB7 in resistant cell lines was validated by immunohistochemistry. To examine its function in chemoresistance, we silenced the gene by RNA interference (RNAi) in doxorubicin-resistant MCF-7 breast cancer cells, then cell vitality was measured after doxorubicin treatment. Microarray gene expression from GEO raw microarray samples with available progression-free survival data was downloaded, and expression of PSMB7 was used for grouping samples.
After doxorubicin treatment, 79.8+/-13.3% of resistant cells survived. Silencing of PSMB7 in resistant cells decreased survival to 31.8+/-6.4% (P>0.001). A similar effect was observed after paclitaxel treatment. In 1592 microarray samples, the patients with high PSMB7 expression had a significantly shorter survival than the patients with low expression (P<0.001).
Our findings suggest that high PSMB7 expression is an unfavourable prognostic marker in breast cancer.
迄今为止，个体标志物未能准确预测乳腺癌对抗癌药物的耐药性。我们使用归因于化疗耐药细胞的基因表达模式来检测与蒽环类药物耐药相关的潜在新生物标志物。其中一个基因 PSMB7 被选作进一步的功能研究和临床验证。
我们对比了四对不同人肿瘤细胞系及其对多柔比星耐药的对应细胞系的表达谱。通过免疫组织化学验证了 PSMB7 在耐药细胞系中的过表达。为了研究其在化疗耐药中的功能，我们通过 RNA 干扰（RNAi）沉默多柔比星耐药 MCF-7 乳腺癌细胞中的基因，然后在多柔比星处理后测量细胞活力。从具有可用无进展生存期数据的 GEO 原始微阵列样本中下载微阵列基因表达，并使用 PSMB7 的表达对样本进行分组。
多柔比星处理后，耐药细胞中有 79.8+/-13.3%存活。在耐药细胞中沉默 PSMB7 可将存活率降低至 31.8+/-6.4%（P>0.001）。紫杉醇处理后也观察到类似的效果。在 1592 个微阵列样本中，高 PSMB7 表达的患者的生存时间明显短于低表达的患者（P<0.001）。
我们的研究结果表明，高 PSMB7 表达是乳腺癌的不良预后标志物。
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