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@article{Harrod:2022:10.1038/s41388-022-02483-8,
author = {Harrod, A and Lai, C and Goldsbrough, I and Simmons, G and Oppermans, N and Santos, D and Gyorffy, B and Allsopp, R and Toghill, B and Balachandran, K and Lawson, M and Morrow, C and Surakala, M and Carnevalli, L and Zhang, P and Guttery, D and Shaw, J and Coombes, RC and Buluwela, L and Ali, S},
doi = {10.1038/s41388-022-02483-8},
journal = {Oncogene},
pages = {4905--4915},
title = {Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer},
url = {http://dx.doi.org/10.1038/s41388-022-02483-8},
volume = {41},
year = {2022}
}

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TY  - JOUR
AB  - 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 mediatedgenome 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-responsivegenes, 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 geneexpression profiles in ER mutant cells predicts clinical response in breast cancer patients withER mutations
AU  - Harrod,A
AU  - Lai,C
AU  - Goldsbrough,I
AU  - Simmons,G
AU  - Oppermans,N
AU  - Santos,D
AU  - Gyorffy,B
AU  - Allsopp,R
AU  - Toghill,B
AU  - Balachandran,K
AU  - Lawson,M
AU  - Morrow,C
AU  - Surakala,M
AU  - Carnevalli,L
AU  - Zhang,P
AU  - Guttery,D
AU  - Shaw,J
AU  - Coombes,RC
AU  - Buluwela,L
AU  - Ali,S
DO  - 10.1038/s41388-022-02483-8
EP  - 4915
PY  - 2022///
SN  - 0950-9232
SP  - 4905
TI  - Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer
T2  - Oncogene
UR  - http://dx.doi.org/10.1038/s41388-022-02483-8
UR  - https://www.nature.com/articles/s41388-022-02483-8
UR  - http://hdl.handle.net/10044/1/99787
VL  - 41
ER  -

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