Defining super-enhancer landscape in triple-negative breast cancer by multiomic profiling

Abstract

Breast cancer is a heterogeneous disease, affecting over 3.5 million women worldwide, yet the functional role of cis-regulatory elements including super-enhancers in different breast cancer subtypes remains poorly characterized. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis.

ANLN Enhances Triple-Negative Breast Cancer Stemness Through TWIST1 and BMP2 and Promotes its Spheroid Growth

“…Whole cell lysates were subjected to Immunoblotting analysis. **, p < 0.01. regulated by super-enhancer (Huang et al, 2021). In the present study, we examined the functional role of ANLN in TNBC by knocking out the gene using Crispr/Cas9 approach.…”

“…By leveraging the TNBC-specific epigenomic data, we recently identified ANLN as a TNBC-specific gene regulated by super-enhancer ( Huang et al, 2021 ). In the present study, we examined the functional role of ANLN in TNBC by knocking out the gene using Crispr/Cas9 approach.…”

“…The specific function of ANLN in TNBC and the molecular mechanism by which ANLN is being regulated, however, is elusive. Our recent study provided direct evidence that TNBC-specific super-enhancer drives ANLN expression, and promotes TNBC clonogenicity ( Huang et al, 2021 ), a sensitive indicator of undifferentiated CSCs. Owing to their clinical implications in metastasis, drug resistance and aggressiveness of tumor ( Korkaya et al, 2012 ; Batlle and Clevers, 2017 ), it is important to dissect mechanisms of CSC maintenance.…”

“…The enrichment of super-enhancers in different subtypes of breast cancer, however, has not been determined. To address heterogeneity of super-enhancers and their functional role in breast cancer, we recently reported a multiomic study employing ChIPseq profiling, gene expression data and network-based analyses to uncover TNBC-specific super-enhancer landscape ( Huang et al, 2021 ). Using Crispr/Cas9 editing, we further demonstrated the functional significance of super-enhancer in driving the expression of key oncogenes FOXC1 and MET in TNBC.…”

Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

“…Cancer specific regulation of transcription is manifested through ectopic activity of proximal and/or distal Regulatory Elements (REs) [1][2][3][4][5]. REs are divided into proximal or cis-acting regulatory elements (CREs), such as promoters, and distal or trans-acting regulatory elements (TREs) comprising of enhancers that establish physical contact with the former via long range 3D chromatin loops [6,7].…”