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Cancer Cell. 2018 Feb 12;33(2):173-186.e5. doi: 10.1016/j.ccell.2018.01.004.

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

Author information

1
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.
2
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
3
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.
4
Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02210, USA; Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215, USA.
5
Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02210, USA.
6
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02215, USA.
7
PamGene International BV, Hertogenbosch 5211, the Netherlands.
8
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02210, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
9
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; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
10
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.
11
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: myles_brown@dfci.harvard.edu.

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.

KEYWORDS:

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

PMID:
29438694
PMCID:
PMC5813700
DOI:
10.1016/j.ccell.2018.01.004
[Indexed for MEDLINE]
Free PMC Article

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