PDF(Pubmed)
Abstract：
Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Understanding the molecular mechanisms is thus key to optimize the existing drugs and to develop new ER-modulators. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities (https://estrogeneii.web.app/). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed substantial diversity in response to different classes of ER-modulators including SERMs, SERDs, SERCA and LDD/PROTAC. Notably, endocrine resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signaling, which is recapitulated clinically. Furthermore, dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of genome-edited versus ectopic overexpression model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer\'s response to endocrine therapies and explore resistance mechanisms.
摘要：
针对雌激素受体（ER/ESR1）的内分泌疗法是治疗ER阳性乳腺癌患者的基石。但是阻力往往限制了它们的有效性。因此，了解分子机制是优化现有药物和开发新的ER调节剂的关键。尽管报告数据的分散方式减少了其潜在影响，但已经取得了显著进展。这里,我们介绍EstroGene2.0，它的前身1.0版本的扩展数据库。EstroGene2.0专注于乳腺癌模型中对内分泌疗法的反应和抗性。整合了来自28个细胞系的212项研究的361个实验的多维分析，用户友好的浏览器提供全面的数据可视化和元数据挖掘功能(https://estrogeneii。Web。app/)。利用统一的数据收集，我们的后续荟萃分析显示，对不同类型的ER调节剂（包括SERM）的反应存在很大差异，SERD,SERCA和LDD/PROTAC。值得注意的是,内分泌抗性模型表现出一系列转录组改变，包括ER和干扰素信号的反向移位，这是临床上概括的。此外，解剖多个ESR1突变细胞模型揭示了基因组编辑与异位过表达模型工程的不同临床相关性，并确定了高置信度突变ER靶标，例如NPY1R。这些例子证明了EstroGene2.0如何帮助研究乳腺癌对内分泌疗法的反应并探索耐药机制。
