小柯机器人

美国纪念斯隆-凯特琳癌症中心Eneda Toska、José Baselga、Christina S. Leslie等研究人员合作发现，ARID1A决定雌激素受体阳性（ER⁺）乳腺癌的管腔身份和治疗反应。2020年1月13日，《自然—遗传学》在线发表了这项成果。

研究人员发现，在晚期内分泌抵抗性ER⁺乳腺癌中存在高频率的ARID1A失活突变。一个表观基因组CRISPR–CAS9敲除（KO）筛选将ARID1A确定为最佳候选基因，其缺失决定了对ER降解剂氟维司群的抗性。细胞和患者中的ARID1A失活通过促进从依赖于ER的管腔细胞向依赖于ER的基底样细胞的转换而导致对ER降解子的抗性。细胞可塑性由ARID1A依赖的SWI/SNF复合物丢失靶向决定腔内谱系的转录因子（包括ER，FOXA1和GATA结合因子3）的基因组位点而介导。ARID1A还调节全基因组的ER–FOXA1染色质相互作用和ER依赖性转录。总之，研究人员发现了ARID1A在维持ER⁺乳腺癌中的管腔细胞身份和内分泌治疗反应中的关键作用。

据介绍，SWI/SNF染色质重塑复合物的亚基ARID1A中的突变是ER⁺乳腺癌中该复合物最常见的变化。

附：英文原文

Title: ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer

Author: Guotai Xu, Sagar Chhangawala, Emiliano Cocco, Pedram Razavi, Yanyan Cai, Jordan E Otto, Lorenzo Ferrando, Pier Selenica, Erik Ladewig, Carmen Chan, Arnaud Da Cruz Paula, Matthew Witkin, Yuanming Cheng, Jane Park, Cristian Serna-Tamayo, HuiYong Zhao, Fan Wu, Mirna Sallaku, Xuan Qu, Alison Zhao, Clayton K Collings, Andrew R. DAvino, Komal Jhaveri, Richard Koche, Ross L. Levine, Jorge S. Reis-Filho, Cigall Kadoch, Maurizio Scaltriti, Christina S. Leslie, Jos Baselga, Eneda Toska

Issue&Volume: 2020-01-13

Abstract: Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common alterations of the SWI/SNF complex in estrogen-receptor-positive (ER+) breast cancer. We identify that ARID1A inactivating mutations are present at a high frequency in advanced endocrine-resistant ER+ breast cancer. An epigenome CRISPR–CAS9 knockout (KO) screen identifies ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A inactivation in cells and in patients leads to resistance to ER degraders by facilitating a switch from ER-dependent luminal cells to ER-independent basal-like cells. Cellular plasticity is mediated by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the luminal lineage-determining transcription factors including ER, forkhead box protein A1 (FOXA1) and GATA-binding factor 3 (GATA3). ARID1A also regulates genome-wide ER–FOXA1 chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in maintaining luminal cell identity and endocrine therapeutic response in ER+ breast cancer.

DOI: 10.1038/s41588-019-0554-0

Source: https://www.nature.com/articles/s41588-019-0554-0

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex