Comparative epigenetic analyses reveal distinct patterns of oncogenic pathways activation in breast cancer subtypes

Abstract

Breast cancer is a highly heterogeneous disease that is characterized by genetic and epigenetic aberrations; however, our knowledge of epigenetic alterations of breast cancer subtypes remains limited. Here, we portrayed and compared the alterations of six types of histone modifications and DNA methylation between two breast cancer subtypes, luminal and basal. Widespread subtype-specific epigenetic alterations were observed in both subtypes, which preferentially occurred within CpG islands (CGIs) and promoter regions. Specifically, aberrant DNA methylation was mostly located inside CGIs in luminal subtype, whereas in basal subtype it was principally located within CGI shores. Moreover, different types and combinatorial patterns of epigenetic alterations were found to occupy at promoter regions between these two subtypes. And these epigenetic alterations regulated corresponding gene expression in a synergetic way in both subtypes. Functional enrichment analysis highlighted that epigenetically dysregulated genes were significantly involved in the hallmarks of cancers, most of which were subtype specific. Even genes involved in the same hallmarks associated biological processes were affected by various types of epi-modifications in different subtypes. Finally, we revealed distinct patterns of oncogenic pathways activation in different subtypes and provided novel insights into subtype specific therapeutic opportunities. In addition, genes in the key signaling pathways were able to discriminate between disease phenotypes, and subtype-specific progression associated genes were identified. This study presents the aberrant epigenetic patterns of breast cancer subtypes at a genome-wide level, which will be a highly valuable resource for investigations at understanding epigenetic regulation of breast cancer subtypes.

Methylation pattern of preferentially expressed antigen of melanoma in acute myeloid leukemia and myelodysplastic syndromes

“…It has previously been revealed the majority of patients with AML1-ETO + AML and a certain number of patients with MDS overexpressed PRAME with abnormally high increases (10,12,13); however, to the best of our knowledge, no previous studies have investigated the effect of methylation on PRAME overexpression. Previous studies reported that the methylation pattern may be associated with the subtype of disease (32). In the present study, the comparison performed between patients with AML1-ETO + AML and MDS with comparably high PRAME transcript levels demonstrated that their methylation patterns were not the same.…”

The Epigenetic Landscape of Promoter Genome-wide Analysis in Breast Cancer

“…H3K27me3 mark enriched in Luminal A and B1 subtypes and involved in dysregulation of subtype-specific gene expression. The impact of histone modifications on gene regulation patterns has been reported in different breast cancer subtypes 19–21 . However, due to difficulty of working with patient tissue sample, the majority of investigations have been carried out in breast cancer cell lines 21, 22 .…”

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer

“…The role of misregulation of selective covalent histone modifications in the onset and progression of cancer malignancies is becoming more and more apparent (17,29,35). These epigenetic changes are regulated, in part, by histone deacetylases (HDACs).…”