Evidence is emerging that long noncoding RNAs (lncRNAs) may play a role in cancer development, but this role is not yet clear. Researchers from the ULB–Cancer Research Center performed a genome-wide transcriptional survey to explore the lncRNA landscape across 995 breast tissue samples. They 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, they identified no less than 210 lncRNAs prognostic of clinical outcome. By analyzing the coexpression of lncRNA genes and protein-coding genes, they inferred potential functions of the 215 dysregulated lncRNAs. The researchers 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, the researchers showed that a specific lncRNA, which they called CYTOR, plays a role in breast cancer. They 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, this work provides the most comprehensive analyses for lncRNA in breast cancers. These 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.
(A) Dendrogram of 823 primary tumors and 172 normal samples obtained by consensus hierarchical clustering of the samples on the basis of expression of the top 500 most variant lncRNAs. Clusters I and III, encompassing almost all tumors, are related to the ER status. (B) Box plot illustrating the expression levels of five lncRNA genes differentially expressed between ER+ and ER− tissues. Notches are used to compare groups; if the notches of two boxes do not overlap, the medians differ significantly. The whiskers extend to the most extreme data point, which is no more than 1.5 times the interquartile range of the box. (C) Heat map illustrating the expression of the 38 lncRNA genes (rows) of the ER signature across the breast tumors (columns). The lncRNAs in bold represent lncRNAs dysregulated between breast cancer and normal samples. The color scale of the heat map indicates the relative expression of each lncRNA gene. Hierarchical clustering reveals three clusters of lncRNAs. For each cluster, the most significant functional enrichment term from the guilt-by-association analysis is shown.