Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Mutations in the estrogen receptor (ESR1) gene are common in ER-positive breast cancer patients who progress on endocrine therapies. Most mutations localise to just three residues at, or near, the C-terminal helix 12 of the hormone binding domain, at leucine-536, tyrosine-537 and aspartate-538. To investigate these mutations, we have used CRISPR-Cas9 mediated
genome engineering to generate a comprehensive set of isogenic mutant breast cancer cell lines. Our results confirm that L536R, Y537C, Y537N, Y537S and D538G mutations confer estrogen-independent growth in breast cancer cells. Growth assays show mutation-specific reductions in sensitivities to drugs representing three classes of clinical anti-estrogens. These differential mutation- and drug-selectivity profiles have implications for treatment choices following clinical emergence of ER mutations. Our results further suggest that mutant expression levels may be determinants of the degree of resistance to some anti-estrogens. Differential gene expression analysis demonstrates up-regulation of estrogen-responsive
genes, as expected, but also reveals that enrichment for interferon-regulated gene expression is a common feature of all mutations. Finally, a new gene signature developed from the gene
expression profiles in ER mutant cells predicts clinical response in breast cancer patients with
ER mutations
genome engineering to generate a comprehensive set of isogenic mutant breast cancer cell lines. Our results confirm that L536R, Y537C, Y537N, Y537S and D538G mutations confer estrogen-independent growth in breast cancer cells. Growth assays show mutation-specific reductions in sensitivities to drugs representing three classes of clinical anti-estrogens. These differential mutation- and drug-selectivity profiles have implications for treatment choices following clinical emergence of ER mutations. Our results further suggest that mutant expression levels may be determinants of the degree of resistance to some anti-estrogens. Differential gene expression analysis demonstrates up-regulation of estrogen-responsive
genes, as expected, but also reveals that enrichment for interferon-regulated gene expression is a common feature of all mutations. Finally, a new gene signature developed from the gene
expression profiles in ER mutant cells predicts clinical response in breast cancer patients with
ER mutations
Date Issued
2022-10-05
Date Acceptance
2022-09-21
Citation
Oncogene, 2022, 41, pp.4905-4915
ISSN
0950-9232
Publisher
Springer Nature [academic journals on nature.com]
Start Page
4905
End Page
4915
Journal / Book Title
Oncogene
Volume
41
Copyright Statement
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Sponsor
Breast Cancer Care & Breast Cancer Now
Medical Research Council (MRC)
Cancer Research UK
Cancer Research UK
Identifier
https://www.nature.com/articles/s41388-022-02483-8
Grant Number
2014MayPR234
MR/P018521/1
C37/A18784
12011
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
LIGAND-BINDING DOMAIN
ACQUIRED ENDOCRINE RESISTANCE
ACTIVATING ESR1 MUTATIONS
ALPHA MUTATIONS
THERAPEUTIC VULNERABILITIES
AROMATASE INHIBITORS
CELLS
ANTAGONISM
LANDSCAPE
STABILITY
Humans
Female
Receptors, Estrogen
Breast Neoplasms
Estrogen Receptor alpha
Prognosis
Estrogen Antagonists
Mutation
Estrogens
Humans
Breast Neoplasms
Estrogen Antagonists
Receptors, Estrogen
Estrogen Receptor alpha
Estrogens
Prognosis
Mutation
Female
Oncology & Carcinogenesis
1103 Clinical Sciences
1112 Oncology and Carcinogenesis
Publication Status
Published
Date Publish Online
2022-10-05