1. Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer
- Author
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Alison Harrod, Chun-Fui Lai, Isabella Goldsbrough, Georgia M. Simmons, Natasha Oppermans, Daniela B. Santos, Balazs Győrffy, Rebecca C. Allsopp, Bradley J. Toghill, Kirsty Balachandran, Mandy Lawson, Christopher J. Morrow, Manasa Surakala, Larissa S. Carnevalli, Pei Zhang, David S. Guttery, Jacqueline A. Shaw, R. Charles Coombes, Lakjaya Buluwela, Simak Ali, Breast Cancer Care & Breast Cancer Now, Medical Research Council (MRC), and Cancer Research UK
- Subjects
Cancer Research ,Biochemistry & Molecular Biology ,ALPHA MUTATIONS ,Breast Neoplasms ,Genetics ,ANTAGONISM ,Humans ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,ACTIVATING ESR1 MUTATIONS ,Molecular Biology ,Genetics & Heredity ,AROMATASE INHIBITORS ,Science & Technology ,ACQUIRED ENDOCRINE RESISTANCE ,LANDSCAPE ,STABILITY ,Estrogen Receptor alpha ,Estrogen Antagonists ,Estrogens ,1103 Clinical Sciences ,Cell Biology ,Prognosis ,Oncology ,Receptors, Estrogen ,CELLS ,Mutation ,Female ,THERAPEUTIC VULNERABILITIES ,LIGAND-BINDING DOMAIN ,Life Sciences & Biomedicine - 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.
- Published
- 2022