Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilities

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-05-13 DOI:10.1186/s12943-025-02342-6

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

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引用次数: 0

Abstract

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. 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. 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. 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.

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分析三阴性乳腺癌特异性超增强子识别高风险间充质发育亚型和beti靶向脆弱性

超级增强子（SEs）是肿瘤发生的关键调节因子，是溴域和外端结构域抑制剂（BETi）的有希望的靶点。然而，包括三阴性乳腺癌（TNBC）在内的各种实体肿瘤的临床研究表明，BETi的疗效有限。本研究旨在探讨TNBC的SE异质性及其对BETi疗效的影响，以推进BETi的精准治疗策略，提高治疗效果。我们对来自TNBC细胞系和临床样本的H3K27ac ChIP-Seq数据进行了全面分析，整合了多个bulk RNA-Seq、scRNA-Seq和stRNA-Seq数据集，以表征TNBC中的SE景观和异质性。利用各种生物信息学算法、CERES评分和转录因子（tf）的临床预后数据，我们确定了由TNBC特异性se和主调控因子组成的核心转录调控回路（CRCs），表征了不同的TNBC亚型。通过体外和体内模型评估这些不同TNBC亚型中crc的生物学意义及其对BETi敏感性的影响。我们的研究结果显示，与非TNBC和正常乳腺上皮相比，TNBC的SE景观明显不同，这使得TNBC可以根据TNBC特异性SE分类为不同的亚型。重要的是，我们确定了一种高风险的间充质发育亚型，通过细胞系和转录组学分析进行了验证，主要由由主调节因子VAX2和tnbc特异性SE组成的CRC驱动。这种SE-VAX2 CRC对于维持该亚型的恶性特征和增加其对BETi的敏感性至关重要。我们的研究阐明了se在TNBC中的异质性，并确定了由SE-VAX2 CRC驱动的高风险间充质发育亚型。该亚型对BETi更敏感，支持其在TNBC中的精确应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

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