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

Cancer Cell

Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02210, USA; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02210, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02210, USA. Electronic address:

Published: February 2018

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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813700PMC
http://dx.doi.org/10.1016/j.ccell.2018.01.004DOI Listing

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