雌激素受体阳性乳腺癌进化调控格局的功能调查。

IF 29.7 1区 医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2024-09-04 DOI:10.1158/2159-8290.CD-23-1157
Iros Barozzi, Neil Slaven, Eleonora Canale, Rui Lopes, Inês Amorim Monteiro Barbosa, Melusine Bleu, Diana Ivanoiu, Claudia Pacini, Emanuela Mensa', Alfie Chambers, Sara Bravaccini, Sara Ravaioli, Balázs Győrffy, Maria Vittoria Dieci, Giancarlo Pruneri, Giorgio Giacomo Galli, Luca Magnani
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引用次数: 0

摘要

只有少数体细胞改变与激素依赖性乳腺癌(HDBC)的内分泌治疗耐药性有关,这可能是约40%复发的原因。目前尚不清楚在辅助治疗下,HDBC 的演变是否还存在其他机制。在这项研究中,我们采用功能基因组学方法,通过关注12兆字节的非编码DNA,包括克隆增强子、基因启动子和拓扑关联域的边界,剖析顺式调控元件(CRE)对癌症进化的贡献。体外并行表观遗传扰乱(CRISPRi)揭示了这些CREs中许多基因的上下文依赖性作用,特别是对休眠期的进入和内分泌治疗耐药性的影响。对接受内分泌疗法治疗的独特纵向患者队列中的CRE体细胞变化进行分析,发现了可能与耐药性有关的一组有限的非编码变化。总之,我们的数据揭示了内分泌疗法如何引发瞬时特征的出现,这些特征最终可能被利用来阻碍适应过程。
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A Functional Survey of the Regulatory Landscape of Estrogen Receptor-Positive Breast Cancer Evolution.

Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters.

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来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
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