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

Author

Listed:
  • 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
    Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London)

  • 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
    Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital)

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.

Suggested Citation

  • Lesley-Ann Martin & Ricardo Ribas & Nikiana Simigdala & Eugene Schuster & Sunil Pancholi & Tencho Tenev & Pascal Gellert & Laki Buluwela & Alison Harrod & Allan Thornhill & Joanna Nikitorowicz-Buniak , 2017. "Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01864-y
    DOI: 10.1038/s41467-017-01864-y
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