Su Xiaoping, Malouf Gabriel G, Chen Yunxin, Zhang Jianping, Yao Hui, Valero Vicente, Weinstein John N, Spano Jean-Philippe, Meric-Bernstam Funda, Khayat David, Esteva Francisco J
Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Groupe Hospitalier Pitié-Salpêtrière, Department of Medical Oncology, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France.
Oncotarget. 2014 Oct 30;5(20):9864-76. doi: 10.18632/oncotarget.2454.
Accumulating evidence highlights the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. However, the role of lncRNA expression in human breast cancer biology, prognosis and molecular classification remains unknown. Herein, we established the lncRNA profile of 658 infiltrating ductal carcinomas of the breast from The Cancer Genome Atlas project. We found lncRNA expression to correlate with the gene expression and chromatin landscape of human mammary epithelial cells (non-transformed) and the breast cancer cell line MCF-7. Unsupervised consensus clustering of lncRNA revealed four subgroups that displayed different prognoses. Gene set enrichment analysis for cis- and trans-acting lncRNAs showed enrichment for breast cancer signatures driven by master regulators of breast carcinogenesis. Interestingly, the lncRNA HOTAIR was significantly overexpressed in the HER2-enriched subgroup, while the lncRNA HOTAIRM1 was significantly overexpressed in the basal-like subgroup. Estrogen receptor (ESR1) expression was associated with distinct lncRNA networks in lncRNA clusters III and IV. Importantly, almost two thirds of the lncRNAs were marked by enhancer chromatin modifications (i.e., H3K27ac), suggesting that expressed lncRNA in breast cancer drives carcinogenesis through increased activity of neighboring genes. In summary, our study depicts the first lncRNA subtype classification in breast cancer and provides the framework for future studies to assess the interplay between lncRNAs and the breast cancer epigenome.
越来越多的证据表明，长链非编码RNA（lncRNA）在实体瘤中作为生物标志物和治疗靶点具有潜在作用。然而，lncRNA表达在人类乳腺癌生物学、预后及分子分类中的作用仍不清楚。在此，我们建立了来自癌症基因组图谱项目的658例乳腺浸润性导管癌的lncRNA图谱。我们发现lncRNA表达与人类乳腺上皮细胞（未转化）和乳腺癌细胞系MCF-7的基因表达及染色质景观相关。lncRNA的无监督一致性聚类揭示了四个具有不同预后的亚组。对顺式和反式作用lncRNA的基因集富集分析显示，由乳腺癌发生的主要调节因子驱动的乳腺癌特征显著富集。有趣的是，lncRNA HOTAIR在HER2富集亚组中显著过表达，而lncRNA HOTAIRM1在基底样亚组中显著过表达。雌激素受体（ESR1）表达与lncRNA簇III和IV中的不同lncRNA网络相关。重要的是，近三分之二的lncRNA被增强子染色质修饰（即H3K27ac）标记，这表明乳腺癌中表达的lncRNA通过增加邻近基因的活性驱动肿瘤发生。总之，我们的研究描绘了乳腺癌中首个lncRNA亚型分类，并为未来评估lncRNA与乳腺癌表观基因组之间相互作用的研究提供了框架。
