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ESR1 ligand-binding domain mutations in hormone-resistant breast cancer

Nature Genetics volume 45, pages 1439–1445 (2013)Cite this article

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Abstract

Seventy percent of breast cancers express estrogen receptor (ER), and most of these are sensitive to ER inhibition. However, many such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. Molecular dynamics simulations suggest that the structures of the Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit.

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Figure 1: ESR1 mutations in ER-positive metastatic breast cancers.
Figure 2: ERα LBD mutants demonstrate elevated activity in the absence of hormone.
Figure 3: ER antagonists partially inhibit mutant ERα transcriptional activity.
Figure 4: Molecular dynamics–modeled structures of wild-type and mutant forms of ERα.

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Acknowledgements

We would like to thank N. Rosen and C. Sawyers for their insights and critical reading of the manuscript, P. Chi and S. Lowe (MSKCC) for plasmids and J.S. Reis-Filho (MSKCC) for cell lines. S.C. is funded by the Damon Runyon Cancer Research Foundation and a Louis V. Gerstner Jr. Young Investigator Award. M.B. and H.W. are funded by the Starr Cancer Consortium and the Geoffrey Beene Cancer Research Center, respectively. Individual support for this study was also provided by Julie Laub (to C.H.). Molecular dynamics simulations were performed using computational resources awarded to Y.S. by the Argonne Leadership Computing Facility at the Argonne National Laboratory, which is supported by the Office of Science of the US Department of Energy under contract DE-AC02-06CH11357. Y.S. is partially funded by the Toyota Technological Institute at Chicago.

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Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA

    Weiyi Toy, Helen Won, Zhiqiang Li, Kinisha Gala, Michael Berger, José Baselga & Sarat Chandarlapaty

  2. Toyota Technological Institute at Chicago, Chicago, Illinois, USA

    Yang Shen

  3. Ben May Department of Cancer Research, University of Chicago, Chicago, Illinois, USA

    Bradley Green, Sean Fanning & Geoffrey Greene

  4. Department of Surgery, Breast Service, MSKCC, New York, New York, USA

    Rita A Sakr & Tari A King

  5. Weill Cornell Medical College, New York, New York, USA

    Marie Will, Clifford Hudis, José Baselga & Sarat Chandarlapaty

  6. Solid Tumor Division, Department of Medicine, Breast Cancer Medicine Service, MSKCC, New York, New York, USA

    Clifford Hudis & Sarat Chandarlapaty

  7. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

    David Chen & Tetiana Taran

  8. Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA

    Gabriel Hortobagyi

  9. Department of Pathology, MSKCC, New York, New York, USA

    Michael Berger

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  1. Weiyi Toy
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Contributions

S.C., W.T., Y.S., G.G., J.B., G.H. and M.B. conceived and designed the experiments. W.T., Y.S., H.W., B.G., S.F., R.A.S., M.W., Z.L., K.G. and S.C. conducted the experiments. W.T., S.C., Y.S., G.G., M.B., H.W., D.C., T.T., J.B., G.H., T.A.K. and C.H. analyzed the data. W.T., S.C., Y.S. and H.W. wrote the manuscript.

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Correspondence to Sarat Chandarlapaty.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 2–4 (PDF 1954 kb)

Supplementary Table 1

MSKCC set: sequencing analysis of all samples (n = 36), matched pairs (n = 22) and copy number (n = 36) (XLSX 101 kb)

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Toy, W., Shen, Y., Won, H. et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45, 1439–1445 (2013). https://doi.org/10.1038/ng.2822

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