Abstract
Evidence is emerging that long noncoding RNAs (lncRNAs) may play a role in cancer development, but this role is not yet clear. We performed a genome-wide transcriptional survey to explore the lncRNA landscape across 995 breast tissue samples. We identified 215 lncRNAs whose genes are aberrantly expressed in breast tumors, as compared to normal samples. Unsupervised hierarchical clustering of breast tumors on the basis of their lncRNAs revealed four breast cancer subgroups that correlate tightly with PAM50-defined mRNA-based subtypes. Using multivariate analysis, we identified no less than 210 lncRNAs prognostic of clinical outcome. By analyzing the coexpression of lncRNA genes and protein-coding genes, we inferred potential functions of the 215 dysregulated lncRNAs. We then associated subtype-specific lncRNAs with key molecular processes involved in cancer. A correlation was observed, on the one hand, between luminal A-specific lncRNAs and the activation of phosphatidylinositol 3-kinase, fibroblast growth factor, and transforming growth factor-β pathways and, on the other hand, between basal-like-specific lncRNAs and the activation of epidermal growth factor receptor (EGFR)-dependent pathways and of the epithelial-to-mesenchymal transition. Finally, we showed that a specific lncRNA, which we called CYTOR, plays a role in breast cancer. We confirmed its predicted functions, showing that it regulates genes involved in the EGFR/mammalian target of rapamycin pathway and is required for cell proliferation, cell migration, and cytoskeleton organization. Overall, our work provides the most comprehensive analyses for lncRNA in breast cancers. Our findings suggest a wide range of biological functions associated with lncRNAs in breast cancer and provide a foundation for functional investigations that could lead to new therapeutic approaches.