Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilities
Abstract 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 lim...
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| Format: | Article |
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BMC
2025-05-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-025-02342-6 |
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| author | Qing-shan Chen Rui-zhao Cai Yan Wang Ge-hao Liang Kai-ming Zhang Xiao-Yu Yang Dong Yang De-Chang Zhao Xiao-Feng Zhu Rong Deng Jun Tang |
| author_facet | Qing-shan Chen Rui-zhao Cai Yan Wang Ge-hao Liang Kai-ming Zhang Xiao-Yu Yang Dong Yang De-Chang Zhao Xiao-Feng Zhu Rong Deng Jun Tang |
| author_sort | Qing-shan Chen |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-168caa8a0bdb4ceeaee12b096db9203f |
| institution | OA Journals |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-168caa8a0bdb4ceeaee12b096db9203f2025-08-20T01:52:03ZengBMCMolecular Cancer1476-45982025-05-0124112610.1186/s12943-025-02342-6Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilitiesQing-shan Chen0Rui-zhao Cai1Yan Wang2Ge-hao Liang3Kai-ming Zhang4Xiao-Yu Yang5Dong Yang6De-Chang Zhao7Xiao-Feng Zhu8Rong Deng9Jun Tang10State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterAbstract 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.https://doi.org/10.1186/s12943-025-02342-6Super-enhancersTriple-negative breast cancerHeterogeneityTranscription factors |
| spellingShingle | Qing-shan Chen Rui-zhao Cai Yan Wang Ge-hao Liang Kai-ming Zhang Xiao-Yu Yang Dong Yang De-Chang Zhao Xiao-Feng Zhu Rong Deng Jun Tang Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilities Molecular Cancer Super-enhancers Triple-negative breast cancer Heterogeneity Transcription factors |
| title | Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilities |
| title_full | Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilities |
| title_fullStr | Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilities |
| title_full_unstemmed | Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilities |
| title_short | Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilities |
| title_sort | profiling triple negative breast cancer specific super enhancers identifies high risk mesenchymal development subtype and beti targetable vulnerabilities |
| topic | Super-enhancers Triple-negative breast cancer Heterogeneity Transcription factors |
| url | https://doi.org/10.1186/s12943-025-02342-6 |
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