Abstract
Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. However, to date, cancer profiling has largely focused on protein-coding genes, which comprise <1% of the genome. Here we leverage a compendium of 58,648 long noncoding RNAs (lncRNAs) to subtype 947 breast cancer samples. We show that lncRNA-based profiling categorizes breast tumours by their known molecular subtypes in breast cancer. We identify a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, and investigate the role of the top prioritized oestrogen receptor (ER)-regulated lncRNA, DSCAM-AS1. We demonstrate that DSCAM-AS1 mediates tumour progression and tamoxifen resistance and identify hnRNPL as an interacting protein involved in the mechanism of DSCAM-AS1 action. By highlighting the role of DSCAM-AS1 in breast cancer biology and treatment resistance, this study provides insight into the potential clinical implications of lncRNAs in breast cancer.
Highlights
Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types
After applying an expression filter (at least one fragments per kilobase of transcript per million mapped reads (FPKM) expression in the breast samples in the top 5% based on gene expression level), we identified 437 of the most differentially expressed long noncoding RNAs (lncRNAs) in breast cancer (Supplementary Data 2)
Unsupervised hierarchical clustering of the samples based on expression of these lncRNAs across all breast cancer samples (Methods section) largely separated out the breast cancer samples by PAM50 subtypes[22,23], suggesting that lncRNAs may be contributing to the distinct biology of these subtypes (Fig. 1a)
Summary
Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. Despite the efficacy of endocrine therapy, the majority of breast cancer deaths occur in women with ER-positive breast cancers, because the incidence of ER-positive versus-negative disease is much higher (approximately 80 versus 20%), and because a substantial fraction of women either have inherent or acquired endocrine therapy-resistant disease[11] Taken together, these considerations highlight the pressing need to understand the biology of the ER-driven breast cancers and their mechanism of resistance to endocrine therapy. The mechanism through which ER mediates cancer initiation and progression is an area of intense scientific investigation[12,13,14] that remains incompletely understood In this regard, while substantial research has been focused on ER abnormalities, such as mutations in the gene encoding for ER (ESR1)[14,15] and on the co-existing activation pathways that might mediate resistance, such as HER216, few studies exist that interrogate ER-regulated noncoding RNAs17–21. We set out to perform a comprehensive discovery and investigation of those lncRNAs that are driven by oestrogen in breast cancers drawing from a large human tissue RNA-seq cohort
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