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

被引：148

作者：

Xu, Guotai ^{[1
]}

Chhangawala, Sagar ^{[2
,3
]}

Cocco, Emiliano ^{[1
]}

Razavi, Pedram ^{[1
,4
]}

Cai, Yanyan ^{[5
]}

Otto, Jordan E. ^{[6
,7
]}

Ferrando, Lorenzo ^{[5
,7
,8
]}

Selenica, Pier ^{[5
]}

Ladewig, Erik ^{[1
,2
]}

Chan, Carmen ^{[1
]}

Paula, Arnaud Da Cruz ^{[5
]}

Witkin, Matthew ^{[9
]}

Cheng, Yuanming ^{[10
]}

Park, Jane ^{[9
]}

Serna-Tamayo, Cristian ^{[4
,11
]}

Zhao, HuiYong ^{[12
]}

Wu, Fan ^{[1
]}

Sallaku, Mirna ^{[1
]}

Qu, Xuan ^{[1
]}

Zhao, Alison ^{[1
]}

Collings, Clayton K. ^{[6
,7
,13
]}

D'Avino, Andrew R. ^{[6
,7
,13
]}

Jhaveri, Komal ^{[4
]}

Koche, Richard ^{[9
]}

Levine, Ross L. ^{[1
,4
,9
]}

Reis-Filho, Jorge S. ^{[5
]}

Kadoch, Cigall ^{[6
,7
,12
]}

Scaltriti, Maurizio ^{[1
,5
]}

Leslie, Christina S. ^{[2
]}

Baselga, Jose ^{[1
,4
,14
]}

Toska, Eneda ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Computat & Syst Biol Program, 1275 York Ave, New York, NY 10021 USA

[3] Weill Cornell Grad Sch, Physiol Biophys & Syst Biol Program, New York, NY USA

[4] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[6] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[7] Harvard Med Sch, Boston, MA 02115 USA

[8] Univ Genoa, Dept Internal Med, Genoa, Italy

[9] Mem Sloan Kettering Canc Ctr, Ctr Epigenet Res, 1275 York Ave, New York, NY 10021 USA

[10] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA

[11] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, New York, NY 10029 USA

[12] Mem Sloan Kettering Canc Ctr, Tumor Assessment Core, 1275 York Ave, New York, NY 10021 USA

[13] Broad Inst Harvard & MIT, Cambridge, MA USA

[14] AstraZeneca, Res & Dev Oncol, Gaithersburg, MD USA

来源：

NATURE GENETICS | 2020年 / 52卷 / 02期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

COMPREHENSIVE MOLECULAR PORTRAITS; TRANSCRIPTION FACTORS; SOMATIC MUTATIONS; GENE-EXPRESSION; CHROMATIN; FOXA1; LANDSCAPE; BINDING; RESISTANCE; CARCINOMAS;

D O I：

10.1038/s41588-019-0554-0

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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. A CRISPR-CAS9 screen, analysis of patient data, and functional in vivo and in vitro experiments identify a critical role for ARID1A in determining breast luminal cell identity and endocrine therapeutic response in estrogen-receptor-positive breast cancer.

引用

页码：198 / +

页数：25

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