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研究揭示乳腺癌患者中FOXA1突变的功能
作者:小柯机器人 发布时间:2020/9/4 20:15:15

美国纪念斯隆-凯特琳癌症中心Maurizio Scaltriti和约翰霍普金斯医学院Eneda Toska小组合作取得一项新突破。他们发现乳腺癌患者中FOXA1突变导致了不同染色质构象并影响对治疗的反应。 该项研究成果在线发表在2020年9月3日的《癌细胞》上。

使用临床基因组队列以及乳腺癌模型,研究人员发现FOXA1突变与对芳香化酶抑制剂反应较低相关。从机制上讲,Wing2突变在雌激素刺激下导致ER位点染色质结合增加,并且在不影响染色质可及性的情况下增强了雌激素受体(ER)介导的转录。相比之下,SY242CS可导致新特征的产生,包括赋予其打开不同染色质区域的能力并激活可变的顺反组和转录组。

结构建模显示SY242CS导致构象变化,该构象变化介导与非典型DNA结构域的稳定结合。综上所述,该研究结果提供了对FOXA1突变如何干扰其功能以促进癌症进展和对治疗反应的见解。

研究人员介绍,先锋转录因子FOXA1的突变是ER+乳腺癌的标志。在约5000名乳腺癌患者中检测FOXA1发现了Wing2区的几个热点突变,以及位于第三条β链的乳腺癌特异性突变SY242CS。

附:英文原文

Title: FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer

Author: Amaia Arruabarrena-Aristorena, Jesper L.V. Maag, Srushti Kittane, Yanyan Cai, Wouter R. Karthaus, Erik Ladewig, Jane Park, Srinivasaraghavan Kannan, Lorenzo Ferrando, Emiliano Cocco, Sik Y. Ho, Daisylyn S. Tan, Mirna Sallaku, Fan Wu, Barbara Acevedo, Pier Selenica, Dara S. Ross, Matthew Witkin, Charles L. Sawyers, Jorge S. Reis-Filho, Chandra S. Verma, Ralf Jauch, Richard Koche, José Baselga, Pedram Razavi, Eneda Toska, Maurizio Scaltriti

Issue&Volume: 2020-09-03

Abstract: Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive(ER+) breast cancers. Examining FOXA1 in ~5,000 breast cancer patients identifies several hotspot mutations in the Wing2region and a breast cancer-specific mutation SY242CS, located in the third β strand.Using a clinico-genomically curated cohort, together with breast cancer models, wefind that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically,Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation,and an enhanced ER-mediated transcription without changes in chromatin accessibility.In contrast, SY242CS shows neomorphic properties that include the ability to opendistinct chromatin regions and activate an alternative cistrome and transcriptome.Structural modeling predicts that SY242CS confers a conformational change that mediatesstable binding to a non-canonical DNA motif. Taken together, our results provide insightsinto how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.

DOI: 10.1016/j.ccell.2020.08.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30414-1

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx