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

Author:

Harrod Alison,Lai Chun-Fui,Goldsbrough Isabella,Simmons Georgia M.,Oppermans Natasha,Santos Daniela B.,Győrffy Balazs,Allsopp Rebecca C.ORCID,Toghill Bradley J.,Balachandran Kirsty,Lawson Mandy,Morrow Christopher J.,Surakala Manasa,Carnevalli Larissa S.ORCID,Zhang Pei,Guttery David S.ORCID,Shaw Jacqueline A.ORCID,Coombes R. CharlesORCID,Buluwela LakjayaORCID,Ali SimakORCID

Abstract

AbstractMutations 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.

Funder

Breast Cancer Now

RCUK | Medical Research Council

Cancer Research UK

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Genetics,Molecular Biology

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