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Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype
Qing-Shan Chen1,2, Rui-Zhao Cai1,2, Yan Wang1,2
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
Molecular Cancer
|May 13, 2025
Summary
Super-enhancers (SEs) drive triple-negative breast cancer (TNBC) heterogeneity. A specific SE-VAX2 core regulatory circuit identifies a high-risk subtype sensitive to bromodomain and extra-terminal domain inhibitors (BETi).
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Super-enhancers (SEs) are key in tumorigenesis and potential targets for bromodomain and extra-terminal domain inhibitors (BETi).
- Clinical efficacy of BETi in solid tumors, including triple-negative breast cancer (TNBC), remains limited.
- Understanding SE heterogeneity in TNBC is crucial for advancing precision treatment strategies.
Purpose of the Study:
- To investigate super-enhancer (SE) heterogeneity in triple-negative breast cancer (TNBC).
- To determine the influence of SE landscape on bromodomain and extra-terminal domain inhibitor (BETi) effectiveness.
- To identify novel therapeutic targets and strategies for TNBC treatment.
Main Methods:
- Analysis of H3K27ac ChIP-Seq and RNA-Seq data (bulk, scRNA-Seq, stRNA-Seq) from TNBC samples.
- Bioinformatic identification of TNBC-specific SEs and core transcriptional regulatory circuits (CRCs) involving master transcription factors (TFs).
- In vitro and in vivo validation of CRC biological significance and impact on BETi sensitivity.
Main Results:
- TNBC exhibits a distinct SE landscape, enabling classification into subtypes based on TNBC-specific SEs.
- A high-risk mesenchymal development subtype was identified, driven by a core regulatory circuit (CRC) comprising VAX2 and a TNBC-specific SE.
- This SE-VAX2 CRC is critical for maintaining malignant phenotypes and enhancing sensitivity to BETi in this subtype.
Conclusions:
- TNBC SE heterogeneity can be leveraged to define distinct subtypes.
- The SE-VAX2 CRC defines a high-risk mesenchymal subtype of TNBC.
- This subtype demonstrates increased sensitivity to BETi, supporting precision therapeutic applications.
