Abstract
Breast cancer is a cancer of high complexity and heterogeneity, with differences in prognosis and survival among patients of different subtypes. Copy number variations (CNVs) within enhancers are crucial drivers of tumorigenesis by influencing expression of their targets. In this study, we performed an integrative approach to identify CNA-driven enhancers and their effect on expression of target genes in four breast cancer subtypes by integrating expression data, copy number data and H3K27ac data. We identified 672, 555, 531, 361 CNA-driven enhancer-gene pairs and 280, 189, 113 and 98 CNA-driven enhancer-lncRNA pairs in the Basal-like, Her2, LumA and LumB subtypes, respectively. We then reconstructed a CNV-driven enhancer-lncRNA-mRNA regulatory network in each subtype. Functional analysis showed CNA-driven enhancers play an important role in the progression of breast cancer subtypes by influencing P53 signaling pathway, PPAR signaling pathway, systemic lupus erythematosus and MAPK signaling pathway in the Basal-like, Her2, LumA and LumB subtypes, respectively. We characterized the potentially prognostic value of target genes of CNV-driven enhancer and lncRNA-mRNA pairs in the subtype-specific network. We identified MUM1 and AC016876.1 as prognostic biomarkers in LumA and Basal-like subtypes, respectively. Higher expression of MUM1 with an amplified enhancer exhibited poorer prognosis in LumA patients. Lower expression of AC016876.1 with a deleted enhancer exhibited poorer survival outcomes of Basal-like patients. We also identified enhancer-related lncRNA-mRNA pairs as prognostic biomarkers, including AC012313.2-MUM1 in the LumA, AC026471.4-PLK5 in the LumB, AC027307.2-OAZ1 in the Basal-like and AC022431.1-HCN2 in the Her2 subtypes. Finally, our results highlighted target genes of CNA-driven enhancers and enhancer-related lncRNA-mRNA pairs could act as prognostic markers and potential therapeutic targets in breast cancer subtypes.
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