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

Lesley-Ann Martin (), Ricardo Ribas, Nikiana Simigdala, Eugene Schuster, Sunil Pancholi, Tencho Tenev, Pascal Gellert, Laki Buluwela, Alison Harrod, Allan Thornhill, Joanna Nikitorowicz-Buniak, Amandeep Bhamra, Marc-Olivier Turgeon, George Poulogiannis, Qiong Gao, Vera Martins, Margaret Hills, Isaac Garcia-Murillas, Charlotte Fribbens, Neill Patani, Zheqi Li, Matthew J. Sikora, Nicholas Turner, Wilbert Zwart, Steffi Oesterreich, Jason Carroll, Simak Ali and Mitch Dowsett
Additional contact information
Lesley-Ann Martin: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Ricardo Ribas: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Nikiana Simigdala: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Eugene Schuster: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Sunil Pancholi: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Tencho Tenev: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Pascal Gellert: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Laki Buluwela: Division of Cancer, CRUK Labs, University of London Imperial College
Alison Harrod: Division of Cancer, CRUK Labs, University of London Imperial College
Allan Thornhill: Centre for Cancer Imaging, Institute of Cancer Research
Joanna Nikitorowicz-Buniak: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Amandeep Bhamra: Proteomic Unit, Institute of Cancer Research
Marc-Olivier Turgeon: Division of Cancer Biology, The Institute of Cancer Research
George Poulogiannis: Division of Cancer Biology, The Institute of Cancer Research
Qiong Gao: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Vera Martins: Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital
Margaret Hills: Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital
Isaac Garcia-Murillas: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Charlotte Fribbens: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Neill Patani: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Zheqi Li: Department of Pharmacology and Chemical biology, University of Pittsburgh
Matthew J. Sikora: Department of Pharmacology and Chemical biology, University of Pittsburgh
Nicholas Turner: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research
Wilbert Zwart: Department of Molecular Pathology, Netherlands Cancer Institute
Steffi Oesterreich: Department of Pharmacology and Chemical biology, University of Pittsburgh
Jason Carroll: Cancer Research UK Cambridge Institute, University of Cambridge
Simak Ali: Division of Cancer, CRUK Labs, University of London Imperial College
Mitch Dowsett: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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 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.

Date: 2017
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DOI: 10.1038/s41467-017-01864-y

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