Deciphering the Cancer Cell Resistome: Gene and microRNA Expression Signatures reveal Unique Molecular Targets for Therapeutic Intervention in Etoposide Resistant Breast Cancer

The second leading cause of cancer death for women in the U.S. is breast cancer. Moreover, a significant number of patients with breast tumors acquire resistance to drugs during therapy. To develop targeted therapeutic strategies to combat drug resistance it is essential to understand the basic molecular mechanisms through which cancer cells control sensitivity to chemotherapeutics. To identify new candidate genes and facilitate the discovery of novel drug resistance pathways, we have generated a resistance profile or ?resistome? of etoposide resistant MCF7 breast cancer cells. Differential expression of over 5000 genes (fold change > 2, P value < 0.05) indicate that several drug resistance mechanisms may be operating in these cells, including up-regulation of ABC transporter genes, down-regulation of the drug target and down-regulation of apoptotic genes. Several transcription factors such as RUNX2, SOX9, ETS1 and SMAD3 were up-regulated in the drug resistant cells. Targeted RUNX2 knockdown in the resistant cells using siRNA increased sensitivity to etoposide and also upregulated expression of pro-apoptotic genes indicating that RUNX2 could be a molecular target against etoposide resistance. Differential miRNA (microRNA) expression was observed among the drug resistant and sensitive cells suggesting that miRNA may also play a role in regulation of drug resistance. Hsa-miR-218, which targets ABCC6, was down-regulated in the drug resistant cell line. Transfection of a miR-218 mimic could down-regulate the expression of the efflux pump ABCC6 by 65% in drug resistant cells suggesting that regulation of miRNA may play an important role in etoposide resistance. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.

美国女性癌症相关死亡的第二大诱因是乳腺癌。此外，大量乳腺肿瘤患者在治疗过程中会产生药物耐药性。为开发对抗药物耐药性的靶向治疗策略，阐明癌细胞调控化疗敏感性的核心分子机制至关重要。为鉴定新的候选基因并助力新型耐药通路的发现，我们构建了依托泊苷（etoposide）耐药的MCF7乳腺癌细胞的耐药谱，即耐药组（resistome）。超过5000个基因呈现差异表达（倍数变化>2，P值<0.05），表明此类细胞可能存在多种耐药机制，包括ABC转运蛋白基因的上调、药物靶点的下调以及凋亡相关基因的下调。RUNX2、SOX9、ETS1与SMAD3等多种转录因子在耐药细胞中呈上调表达。通过小干扰RNA（siRNA）对耐药细胞中的RUNX2进行靶向敲低，可提升其对依托泊苷的敏感性，同时上调促凋亡基因的表达，提示RUNX2可作为对抗依托泊苷耐药的分子靶点。耐药细胞与敏感细胞间存在微小RNA（microRNA，miRNA）的差异表达，表明miRNA或也参与药物耐药性的调控。靶向ABCC6的hsa-miR-218在耐药细胞系中呈下调状态。将miR-218模拟物转染至耐药细胞后，可使外排泵ABCC6的表达下调65%，提示miRNA的调控在依托泊苷耐药过程中发挥重要作用。本SuperSeries由下述SubSeries组成，请参阅各独立数据集。