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

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): 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 Houtman, X. Shirley Liu, Ofir Cohen, Nikhil Wagle, Eric P. Winer, Jean Zhao, Myles Brown
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.

Graphical abstract

Teaser

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.


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