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Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.

ABSTRACT: Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-? (ESR1) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study. We report the first discovery of naturally occurring ESR1 Y537C and ESR1 Y537S mutations in MCF7 and SUM44 ESR1-positive cell lines after acquisition of resistance to long-term-estrogen-deprivation (LTED) and subsequent resistance to fulvestrant (ICIR). Mutations were enriched with time, impacted on ESR1 binding to the genome and altered the ESR1 interactome. The results highlight the importance and functional consequence of these mutations and provide an important resource for studying endocrine resistance.

SUBMITTER: Martin LA

PROVIDER: S-EPMC5709387 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.

Martin Lesley-Ann LA Ribas Ricardo R Simigdala Nikiana N Schuster Eugene E Pancholi Sunil S Tenev Tencho T Gellert Pascal P Buluwela Laki L Harrod Alison A Thornhill Allan A Nikitorowicz-Buniak Joanna J Bhamra Amandeep A Turgeon Marc-Olivier MO Poulogiannis George G Gao Qiong Q Martins Vera V Hills Margaret M Garcia-Murillas Isaac I Fribbens Charlotte C Patani Neill N Li Zheqi Z Sikora Matthew J MJ Turner Nicholas N Zwart Wilbert W Oesterreich Steffi S Carroll Jason J Ali Simak S Dowsett Mitch M

Nature communications 20171130 1

Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α (ESR1) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study. We report the first discovery of naturally occurring ES ...[more]

PMID: 29192207

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Project description:BACKGROUND:Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. METHODS:The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays. RESULTS:Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib. CONCLUSION:ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.

Dataset Information

Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.

Publications

Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.

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