Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations

Jeselsohn Rinath; Bergholz Johann S.; Pun Matthew; Cornwell MacIntosh; Liu Weihan; Nardone Agostina; Xiao Tengfei; Li Wei; Qiu Xintao; Buchwalter Gilles; Feiglin Ariel; Abell-Hart Kayley; Fei Teng; Rao Prakash; Long Henry; Kwiatkowski Nicholas; Zhang Tinghu; Gray Nathanael; Melchers Diane; Houtman Rene; Liu X. Shirley; Cohen Ofir; Wagle Nikhil; Winer Eric P.; Zhao Jean; Brown Myles

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Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations

机译：等位基因特异性染色质招募和治疗脆弱性ESR1激活突变

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Estrogen receptor a (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistantmetastatic ER-positive (ER+) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic targets.

机译：雌激素受体A（ER）配体结合结构域（LBD）突变在大量的内分泌治疗抵抗致抗体（ER +）乳腺癌中发现。我们调查了患有临床相关的ER突变的乳腺癌模型中的染色质招生，转录网络和遗传脆弱性。这些突变体表现出与促进雌二醇结合的野生型ER的配体无关的函数，以及促进促进促型转移表型的等位基因特异性新立方性。分析基因组叠层结合位点鉴定突变体ER独特募集介质等位基因特异性转录程序。遗传筛鉴定了对由突变体驱动的配体无关的生长至关重要的基因。这些研究提供了ET突变和潜在治疗靶标的内分泌治疗抗性机制的见解。

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《Cancer Cell》 |2018年第2期|共19页
作者
Jeselsohn Rinath; Bergholz Johann S.; Pun Matthew; Cornwell MacIntosh; Liu Weihan; Nardone Agostina; Xiao Tengfei; Li Wei; Qiu Xintao; Buchwalter Gilles; Feiglin Ariel; Abell-Hart Kayley; Fei Teng; Rao Prakash; Long Henry; Kwiatkowski Nicholas; Zhang Tinghu; Gray Nathanael; Melchers Diane; Houtman Rene; Liu X. Shirley; Cohen Ofir; Wagle Nikhil; Winer Eric P.; Zhao Jean; Brown Myles;
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Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Harvard Med Sch Boston MA 02210 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

PamGene Int BV NL-5211 sHertogenbosch Netherlands;

PamGene Int BV NL-5211 sHertogenbosch Netherlands;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02210 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02210 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02210 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Dana Farber Canc Inst Ctr Funct Canc Epigenet Boston MA 02210 USA;

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专利

1. Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations [J] . Jeselsohn Rinath, Bergholz Johann S., Pun Matthew, Cancer Cell . 2018,第2期

机译：等位基因特异性染色质招募和治疗脆弱性ESR1激活突变
2. BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations [J] . Qinong Ye, Yan-Fen Hu, Hongjun Zhong, Journal of cell biology . 2001,第6期

机译：BRCA1诱导的大规模染色质展开和癌症易感突变的等位基因特异性作用
3. Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex. [J] . Atkinson SD, McGilligan VE, Liao H, The Journal of investigative dermatology. . 2011,第10期

机译：开发用于大疱表皮松解中角蛋白5突变的等位基因特异性治疗性siRNA。
4. A Single Tube Screening of Endocrine Therapy Resistance ESR1 Mutations in ER-Positive Breast Cancer [C] . Akihiro Tsuyada, Shunsuke Nakano, Toshimitsu Ichijo, International Molecular Medicine Tri-Conference. . 2016

机译：ER阳性乳腺癌内分泌治疗抗ESR1突变的单管筛选
5. Mechanisms of Action of Non-canonical ESR1 Ligand Domain Mutations Identified in Breast Cancer [D] . Gadiya, Mayur 2020

机译：乳腺癌中非规范性ESR1配体域突变的作用机制。
6. Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations [O] . Rinath Jeselsohn, Johann S Bergholz, Matthew Pun, -1

机译：等位基因特异性染色质募集和ESR1激活突变的治疗脆弱性
7. Prioritization of enhancer mutations by combining allele-specific chromatin accessibility with deep learning [O] . Zeynep Kalender Atak, Ibrahim Ihsan Taskiran, Christopher Flerin, 2019

机译：通过与深度学习结合等位基因特异性染色蛋白可接近性，增强剂突变的优先级

Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations

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