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Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
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.
Background:
Super-enhancers (SEs) are critical regulators of tumorigenesis and represent promising targets for bromodomain and extra-terminal domain inhibitors (BETi). However, clinical studies across various solid tumors, including triple-negative breast cancer (TNBC), have demonstrated limited BETi efficacy. This study aims to investigate SE heterogeneity in TNBC and its influence on BETi effectiveness, with the goal of advancing BETi precision treatment strategies and enhancing therapeutic efficacy.
Methods:
We conducted a comprehensive analysis of H3K27ac ChIP-Seq data from TNBC cell lines and clinical samples, integrating multiple bulk RNA-Seq, scRNA-Seq, and stRNA-Seq datasets to characterize the SE landscape and heterogeneity in TNBC. Utilizing various bioinformatics algorithms, CERES scoring, and clinical prognostic data on transcription factors (TFs), we identified core transcriptional regulatory circuits (CRCs) composed of TNBC-specific SEs and master regulators, characterizing different TNBC subtypes. The biological significance of CRCs in these different TNBC subtypes and their influence on BETi sensitivity were evaluated using in vitro and in vivo models.
Results:
Our findings revealed a distinct SE landscape in TNBC compared to non-TNBC and normal breast epithelium, allowing TNBC to be classified into distinct subtypes based on TNBC-specific SEs. Importantly, we identified a high-risk mesenchymal development subtype, validated across cell lines and transcriptomic analyses, primarily driven by a CRC consisting of the master regulator VAX2 and a TNBC-specific SE. This SE-VAX2 CRC is essential for sustaining the malignant traits of this subtype and increasing its sensitivity to BETi.
Conclusions:
Our research clarifies the heterogeneity of SEs in TNBC and identifies a high-risk mesenchymal development subtype driven by the SE-VAX2 CRC. The subtype shows more sensitivity to BETi, supporting its precision application in TNBC.
Insights
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.
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