Global MicroRNA Expression Profiling Identifies MiR-210 Associated with Tumor Proliferation, Invasion and Poor Clinical Outcome in Breast Cancer

PurposeAberrant microRNA (miRNA) expression is associated with cancer and has potential diagnostic and prognostic value in various malignancies. In this study, we investigated miRNA profiling as a complementary tool to improve our understanding of breast cancer (BC) biology and to assess whether miRNA expression could predict clinical outcome of BC patients. Experimental DesignGlobal miRNA expression profiling using microarray technology was conducted in 56 systemically untreated BC patients who had corresponding mRNA expression profiles available. Results were further confirmed using qRT-PCR in an independent dataset of 89 ER-positive BC patients homogeneously treated with tamoxifen only. MiR-210 functional analyses were performed in MCF7 and MDA-MB-231 BC cell lines using lentiviral transduction. ResultsEstrogen receptor (ER) status, tumor grade and our previously developed gene expression grade index (GGI) were associated with distinct miRNA profiles. Several miRNAs were found to be clinically relevant, including miR-210, its expression being associated with tumor proliferation and differentiation. Furthermore, miR-210 was associated with poor clinical outcome in ER-positive, tamoxifen-treated BC patients. Interestingly, the prognostic performance of miR-210 was similar to several reported multi-gene signatures, highlighting its important role in BC differentiation and tumor progression. Functional analyses in BC cell lines revealed that miR-210 is involved in cell proliferation, migration and invasion. ConclusionsThis integrated analysis combining miRNA and mRNA expression demonstrates that miRNA expression provides additional biological information beyond mRNA expression. Expression of miR-210 is linked to tumor proliferation and appears to be a strong potential biomarker of clinical outcome in BC.研究目的：异常表达的微小RNA（microRNA）与癌症密切相关，在多种恶性肿瘤中具备潜在的诊断与预后价值。本研究旨在通过miRNA表达谱分析，加深对乳腺癌（breast cancer，BC）生物学特性的理解，并评估miRNA表达能否预测乳腺癌患者的临床结局。 实验设计：本研究采用微阵列技术，对56例未接受系统治疗且具备匹配mRNA表达谱的乳腺癌患者进行全miRNA表达谱检测。随后，在包含89例仅接受他莫昔芬单一治疗的雌激素受体阳性（estrogen receptor，ER）乳腺癌患者的独立队列中，通过实时荧光定量逆转录PCR（qRT-PCR）验证了上述结果。本研究还采用慢病毒转导技术，在MCF7与MDA-MB-231乳腺癌细胞系中开展miR-210的功能分析。 研究结果：雌激素受体（ER）状态、肿瘤分级以及本团队此前开发的基因表达分级指数（gene expression grade index，GGI）与特征性miRNA表达谱显著相关。研究发现多种miRNA具有临床相关性，其中miR-210的表达与肿瘤增殖及分化密切相关。进一步分析显示，在仅接受他莫昔芬治疗的ER阳性乳腺癌患者中，miR-210高表达与不良临床结局显著相关。值得注意的是，miR-210的预后预测性能与多项已报道的多基因特征相当，凸显了其在乳腺癌分化及肿瘤进展中的关键作用。乳腺癌细胞系的功能实验结果表明，miR-210参与调控细胞增殖、迁移与侵袭过程。 研究结论：本项整合miRNA与mRNA表达的综合分析表明，miRNA表达能够提供mRNA表达之外的额外生物学信息。miR-210的表达与肿瘤增殖密切相关，有望成为乳腺癌临床结局的强效潜在生物标志物。