Dataset Information

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

ABSTRACT: Estrogen receptor ? (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic 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.

SUBMITTER: Jeselsohn R

PROVIDER: S-EPMC5813700 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Jeselsohn Rinath R Bergholz Johann S JS Pun Matthew M Cornwell MacIntosh M Liu Weihan W Nardone Agostina A Xiao Tengfei T Li Wei W Qiu Xintao X Buchwalter Gilles G Feiglin Ariel A Abell-Hart Kayley K Fei Teng T Rao Prakash P Long Henry H Kwiatkowski Nicholas N Zhang Tinghu T Gray Nathanael N Melchers Diane D Houtman Rene R Liu X Shirley XS Cohen Ofir O Wagle Nikhil N Winer Eric P EP Zhao Jean J Brown Myles M

Cancer cell 20180201 2

Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER<sup>+</sup>) 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 t ...[more]

PMID: 29438694

Dataset Information

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

Publications

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

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