[PDF][PDF] Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations

R Jeselsohn, JS Bergholz, M Pun, MI Cornwell, W Liu… - Cancer cell, 2018 - cell.com
R Jeselsohn, JS Bergholz, M Pun, MI Cornwell, W Liu, A Nardone, T Xiao, W Li, X Qiu
Cancer cell, 2018cell.com
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 …
Summary
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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