Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer.

Autor: Harrod A; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK.; Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK., Lai CF; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK., Goldsbrough I; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK., Simmons GM; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK., Oppermans N; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK., Santos DB; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK., Győrffy B; Semmelweis University Department of Bioinformatics, H-1094 Budapest, Hungary and TTK Cancer Biomarker Research Group, H-1117, Budapest, Hungary., Allsopp RC; Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK., Toghill BJ; Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK., Balachandran K; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK., Lawson M; Early Oncology R&D, AstraZeneca, Biomedical Campus, 1 Francis Crick Ave, Cambridge, CB2 0AA, UK., Morrow CJ; Early Oncology R&D, AstraZeneca, Biomedical Campus, 1 Francis Crick Ave, Cambridge, CB2 0AA, UK., Surakala M; Early Oncology R&D, AstraZeneca, Biomedical Campus, 1 Francis Crick Ave, Cambridge, CB2 0AA, UK., Carnevalli LS; Early Oncology R&D, AstraZeneca, Biomedical Campus, 1 Francis Crick Ave, Cambridge, CB2 0AA, UK., Zhang P; Early Oncology R&D, AstraZeneca, Biomedical Campus, 1 Francis Crick Ave, Cambridge, CB2 0AA, UK., Guttery DS; Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK., Shaw JA; Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK., Coombes RC; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK., Buluwela L; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK. l.buluwela@imperial.ac.uk., Ali S; Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK. simak.ali@imperial.ac.uk.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 Oct; Vol. 41 (44), pp. 4905-4915. Date of Electronic Publication: 2022 Oct 05.
DOI: 10.1038/s41388-022-02483-8
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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