PO.MCB06.04 · 分子与细胞生物学
整合表观基因组图谱分析揭示驱动雌激素受体阳性转移性乳腺癌治疗耐药的独特转录因子网络
Integrated epigenomic profiling reveals distinct transcription factor networks driving therapy resistance in estrogen receptor positive metastatic breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：雌激素受体阳性转移性乳腺癌的内分泌治疗耐药机制仍知之甚少，许多耐药肿瘤缺乏可靶向的基因组改变。新出现的证据表明，表观遗传重编程通过转录因子调控网络的重连来驱动耐药，然而对耐药肿瘤的全面表观基因组特征描述仍然有限。
方法：我们在具有临床相关性的治疗耐药和敏感的雌激素受体阳性转移性乳腺癌模型中进行了整合的ATAC-seq和RNA-seq图谱分析，包括携带多种基因组改变的患者来源异种移植（PDX）模型以及敏感的乳腺癌细胞系。我们对染色质可及性和基因表达数据应用无监督聚类，以识别非基因组聚类。通过整合可及染色质区域中转录因子结合基序富集与下游靶基因表达网络，识别出主控调节因子（master regulator）。
结果：我们识别出治疗耐药雌激素受体阳性转移性乳腺癌的五个独特表观基因组聚类，每个聚类均由独特的主控转录因子调控程序驱动。聚类1由所有敏感模型（如PDX模型和细胞系）组成，保留了管腔型激素反应特性。治疗耐药肿瘤分化为四个独特程序：聚类2表现为先锋因子（pioneer factor）主导，染色质重塑增强，同时保留部分管腔特征。聚类5代表一种ESR1突变的管腔型HER2杂合状态，伴有ERBB2扩增，结合了改变的雌激素受体信号与受体酪氨酸激酶激活。聚类4通过上皮-间质转化（EMT）表现出间质型耐药。聚类3代表去分化程度最高的表型，即一种伴有FOXA1缺失的炎症性癌症干细胞状态。
结论：我们的整合表观基因组方法揭示，雌激素受体阳性转移性乳腺癌的治疗耐药由四个独特的转录因子驱动调控程序所协调，这些程序通过非遗传性重连而非仅依靠基因组改变而出现。这些聚类涵盖了从先锋因子介导的染色质重塑和管腔-HER2杂合状态到间质可塑性及炎症性干细胞样网络的谱系。重要的是，这些表观遗传聚类可能解释了突变阴性的耐药现象，并揭示了亚型特异性的治疗弱点。这一分子框架为针对耐药转移性乳腺癌表观基因组状态定制的精准医学方法提供了路线图。
查看英文原文 English abstract
Background: Endocrine therapy resistance in estrogen receptor positive metastatic breast cancer remains poorly understood, with many resistant tumors lacking actionable genomic alterations. Emerging evidence suggests epigenetic reprogramming drives resistance through transcription factor regulatory network rewiring, yet comprehensive epigenomic characterization of resistant tumors remains limited.
Methods: We performed integrated ATAC-seq and RNA-seq profiling in clinically relevant models of therapy-resistant and sensitive estrogen receptor positive metastatic breast cancer, including patient-derived xenografts harboring diverse genomic alterations, along with sensitive breast cancer cell lines. We applied unsupervised clustering to chromatin accessibility and gene expression data to identify non-genomic clusters. Master regulators were identified by integrating transcription factor binding motif enrichment in accessible chromatin regions with downstream target gene expression networks.
Results: We identified five distinct epigenomic clusters of therapy-resistant estrogen receptor positive metastatic breast cancer, each driven by unique master transcription factor regulatory programs. Cluster 1, comprising all sensitive models such as patient-derived xenografts and cell lines, retained luminal hormone-responsive identity. Therapy resistant tumors segregated into four distinct programs: Cluster 2 showed pioneer factor dominance with enhanced chromatin remodeling while maintaining partial luminal features. Cluster 5 represented an ESR1 -mutant luminal HER2 hybrid state with ERBB2 amplification, combining altered estrogen receptor signaling with receptor tyrosine kinase activation. Cluster 4 displayed mesenchymal resistance via epithelial-mesenchymal transition. Cluster 3 represented the most dedifferentiated phenotype, an inflammatory cancer stem cell state with FOXA1 loss.
Conclusion: Our integrated epigenomic approach reveals that therapy-resistance in estrogen receptor positive metastatic breast cancer is orchestrated by four distinct transcription factor-driven regulatory programs that emerge through non-genetic rewiring rather than genomic alterations alone. These clusters span a spectrum from pioneer factor-mediated chromatin remodeling and hybrid luminal-HER2 states to mesenchymal plasticity and inflammatory stem-like networks. Importantly, these epigenetic clusters may explain mutation-negative resistance and reveal subtype-specific therapeutic vulnerabilities. This molecular framework provides a roadmap for precision medicine approaches tailored to the epigenomic state of resistant metastatic breast cancer.
利益披露 Disclosure
G. Yayli-Vokshi, None..
S. Cohen, None..
W. Li, None..
H. Shao, None..
S. Bowker, None..
E. de Stanchina, None.