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. 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.
Original language | English |
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Pages (from-to) | 173-186.e5 |
Journal | Cancer Cell |
Volume | 33 |
Issue number | 2 |
DOIs | |
State | Published - 12 Feb 2018 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2018 Elsevier Inc.
Funding
This work was supported in part by grant from the NIH K08 CA191058-03 (to R.J.), the Claudia Adams Barr Program for Innovative Cancer Research (to R.J.), NCI grant P50 CA168504 (SPORE) Career Development Award (to R.J.), a Susan Komen Leadership Grant (to M.B.), and NIH P01CA080111 (to M.B.). This work was supported in part by grant from the NIH K08 CA191058-03 (to R.J.), the Claudia Adams Barr Program for Innovative Cancer Research (to R.J.), NCI grant P50 CA168504 (SPORE) Career Development Award (to R.J.), a Susan Komen Leadership Grant (to M.B.), and NIH P01CA080111 (to M.B.).
Funders | Funder number |
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Susan Komen Leadership | |
National Institutes of Health | K08 CA191058-03 |
National Cancer Institute | P01CA080111, P50 CA168504 |
National Computational Infrastructure |
Keywords
- CDK7
- breast cancer
- cistrome
- endocrine therapy resistance
- estrogen receptor
- estrogen recptor mutations