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

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

Research output: Contribution to journalArticlepeer-review

207 Scopus citations

Abstract

Estrogen receptor α (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. Jeselsohn et al. show that estrogen receptor α (ER) mutations found in endocrine treatment-resistant metastatic breast cancers confer not only ligand-independent ER functions, but also allele-specific neomorphic properties. Importantly, the authors identify potential approaches for treating these breast cancers.

Original languageEnglish
Pages (from-to)173-186.e5
JournalCancer Cell
Volume33
Issue number2
DOIs
StatePublished - 12 Feb 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

Funding

This work was supported in part by grant from the NIH K08 CA191058-03 (to R.J.), the Claudia Adams Barr Program for Innovative Cancer Research (to R.J.), NCI grant P50 CA168504 (SPORE) Career Development Award (to R.J.), a Susan Komen Leadership Grant (to M.B.), and NIH P01CA080111 (to M.B.). This work was supported in part by grant from the NIH K08 CA191058-03 (to R.J.), the Claudia Adams Barr Program for Innovative Cancer Research (to R.J.), NCI grant P50 CA168504 (SPORE) Career Development Award (to R.J.), a Susan Komen Leadership Grant (to M.B.), and NIH P01CA080111 (to M.B.).

FundersFunder number
Susan Komen Leadership
National Institutes of HealthK08 CA191058-03
National Cancer InstituteP01CA080111, P50 CA168504
National Computational Infrastructure

    Keywords

    • CDK7
    • breast cancer
    • cistrome
    • endocrine therapy resistance
    • estrogen receptor
    • estrogen recptor mutations

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