基于超级增强子相关转录调控因子和生物标志物的患者来源三阴性乳腺癌模型分子特征

Super-enhancers (SEs) have been defined as particular genomic regions with clusters of consecutive enhancers, which provide cell- or stage-specific context. SEs are often determined by high-level enrichment for genomic binding of transcriptional coactivators and active chromatin marks such as histone H3 with acetylated K27. In this study, we aim to characterize similarity and specificity of SE-associated gene profiles of patient-derived models of triple-negative breast cancer (TNBC) obtained from distinct advanced cases. We identified SE-associated genes for these models based on the integrated study of RNA-sequencing and chromatin immunoprecipitation (ChIP) sequencing for H3K27ac binding. Since these patient-derived cancer models were generated through a spheroid culture technique, stemness markers such as CD44 and MYC were identified as predominant SE-associated genes in the majority of cases. We further identified MYBL1 as a critical SE-associated transcription factor among basal-like cancer cases. Silencing of MYBL1 in TNBC patient-derived and cell line models showed that this transcription factor contributes to cell proliferation and the regulation of mitosis-associated gene expression. Immunohistochemical study for MYBL1 in our TNBC cohort showed that MYBL1 immunoreactivity is a potential poor prognostic factor for TNBC patients. The present findings suggest that the characterization of SE-associated transcriptional regulators and biomarkers will facilitate the understanding of molecular features of TNBC subtypes and the development of alternative potential therapeutic targets for the advanced disease.