| Literature DB >> 29438694 |
Rinath Jeselsohn1, Johann S Bergholz2, Matthew Pun3, MacIntosh Cornwell3, Weihan Liu3, Agostina Nardone3, Tengfei Xiao3, Wei Li4, Xintao Qiu5, Gilles Buchwalter3, Ariel Feiglin6, Kayley Abell-Hart2, Teng Fei3, Prakash Rao5, Henry Long5, Nicholas Kwiatkowski2, Tinghu Zhang2, Nathanael Gray2, Diane Melchers7, Rene Houtman7, X Shirley Liu4, Ofir Cohen8, Nikhil Wagle9, Eric P Winer10, Jean Zhao2, Myles Brown11.
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.Entities:
Keywords: CDK7; breast cancer; cistrome; endocrine therapy resistance; estrogen receptor; estrogen recptor mutations
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Year: 2018 PMID： 29438694 PMCID： PMC5813700 DOI： 10.1016/j.ccell.2018.01.004
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743