ARID1A決定雌激素受體陽性乳腺癌的管腔身份和治療反應(yīng)
美國紀(jì)念斯隆-凱特琳癌癥中心Eneda Toska、José Baselga、Christina S. Leslie等研究人員合作發(fā)現(xiàn)，ARID1A決定雌激素受體陽性（ER+）乳腺癌的管腔身份和治療反應(yīng)。2020年1月13日，《自然—遺傳學(xué)》在線發(fā)表了這項(xiàng)成果。
研究人員發(fā)現(xiàn)，在晚期內(nèi)分泌抵抗性ER+乳腺癌中存在高頻率的ARID1A失活突變。一個表觀基因組CRISPR–CAS9敲除（KO）篩選將ARID1A確定為較好候選基因，其缺失決定了對ER降解劑氟維司群的抗性。細(xì)胞和患者中的ARID1A失活通過促進(jìn)從依賴于ER的管腔細(xì)胞向依賴于ER的基底樣細(xì)胞的轉(zhuǎn)換而導(dǎo)致對ER降解子的抗性。細(xì)胞可塑性由ARID1A依賴的SWI/SNF復(fù)合物丟失靶向決定腔內(nèi)譜系的轉(zhuǎn)錄因子（包括ER，F(xiàn)OXA1和GATA結(jié)合因子3）的基因組位點(diǎn)而介導(dǎo)。ARID1A還調(diào)節(jié)全基因組的ER–FOXA1染色質(zhì)相互作用和ER依賴性轉(zhuǎn)錄?？傊?，研究人員發(fā)現(xiàn)了ARID1A在維持ER+乳腺癌中的管腔細(xì)胞身份和內(nèi)分泌治療反應(yīng)中的關(guān)鍵作用。
據(jù)介紹，SWI/SNF染色質(zhì)重塑復(fù)合物的亞基ARID1A中的突變是ER+乳腺癌中該復(fù)合物常見的變化。
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
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