Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

Accession codes

Primary accessions

Gene Expression Omnibus

Referenced accessions

Protein Data Bank

References

  1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687–1717 (2005).

  2. Ariazi, E.A., Ariazi, J.L., Cordera, F. & Jordan, V.C. Estrogen receptors as therapeutic targets in breast cancer. Curr. Top. Med. Chem. 6, 181–202 (2006).

    Article  CAS  Google Scholar 

  3. Strasser-Weippl, K. & Goss, P.E. Advances in adjuvant hormonal therapy for postmenopausal women. J. Clin. Oncol. 23, 1751–1759 (2005).

    Article  CAS  Google Scholar 

  4. Forbes, J.F. et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 9, 45–53 (2008).

    Article  Google Scholar 

  5. Peng, J., Sengupta, S. & Jordan, V.C. Potential of selective estrogen receptor modulators as treatments and preventives of breast cancer. Anticancer. Agents Med. Chem. 9, 481–499 (2009).

    Article  CAS  Google Scholar 

  6. Wagle, N. et al. High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discov. 2, 82–93 (2012).

    Article  CAS  Google Scholar 

  7. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  8. Gutierrez, M.C. et al. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J. Clin. Oncol. 23, 2469–2476 (2005).

    Article  CAS  Google Scholar 

  9. Lipton, A. et al. Serum HER-2/neu conversion to positive at the time of disease progression in patients with breast carcinoma on hormone therapy. Cancer 104, 257–263 (2005).

    Article  CAS  Google Scholar 

  10. Meng, S. et al. HER-2 gene amplification can be acquired as breast cancer progresses. Proc. Natl. Acad. Sci. USA 101, 9393–9398 (2004).

    Article  CAS  Google Scholar 

  11. Jirström, K. et al. Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res. 65, 8009–8016 (2005).

    Article  Google Scholar 

  12. Turner, N. et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70, 2085–2094 (2010).

    Article  CAS  Google Scholar 

  13. Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).

    Article  CAS  Google Scholar 

  14. Nettles, K.W. et al. NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nat. Chem. Biol. 4, 241–247 (2008).

    Article  CAS  Google Scholar 

  15. Zhang, Q.X., Borg, A., Wolf, D.M., Oesterreich, S. & Fuqua, S.A. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 57, 1244–1249 (1997).

    CAS  PubMed  Google Scholar 

  16. Kato, S. et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270, 1491–1494 (1995).

    Article  CAS  Google Scholar 

  17. Le Goff, P., Montano, M.M., Schodin, D.J. & Katzenellenbogen, B.S. Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. J. Biol. Chem. 269, 4458–4466 (1994).

    CAS  PubMed  Google Scholar 

  18. Anzick, S.L. et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277, 965–968 (1997).

    Article  CAS  Google Scholar 

  19. Azorsa, D.O., Cunliffe, H.E. & Meltzer, P.S. Association of steroid receptor coactivator AIB1 with estrogen receptor-α in breast cancer cells. Breast Cancer Res. Treat. 70, 89–101 (2001).

    Article  CAS  Google Scholar 

  20. Fan, M., Park, A. & Nephew, K.P. CHIP (carboxyl terminus of Hsc70–interacting protein) promotes basal and geldanamycin-induced degradation of estrogen receptor-α. Mol. Endocrinol. 19, 2901–2914 (2005).

    Article  CAS  Google Scholar 

  21. Chandarlapaty, S. et al. SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase–dependent cancers. Clin. Cancer Res. 14, 240–248 (2008).

    Article  CAS  Google Scholar 

  22. Shang, Y. & Brown, M. Molecular determinants for the tissue specificity of SERMs. Science 295, 2465–2468 (2002).

    Article  CAS  Google Scholar 

  23. Weis, K.E., Ekena, K., Thomas, J.A., Lazennec, G. & Katzenellenbogen, B.S. Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. Mol. Endocrinol. 10, 1388–1398 (1996).

    CAS  PubMed  Google Scholar 

  24. Brzozowski, A.M. et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389, 753–758 (1997).

    Article  CAS  Google Scholar 

  25. Won, H.H., Scott, S.N., Brannon, A.R., Shah, R.H. & Berger, M.F. Detecting somatic genetic alterations in tumor specimens by exon capture and massively parallel sequencing. J. Vis. Exp. 80, e50710 (2013).

    Google Scholar 

  26. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  Google Scholar 

  27. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  Google Scholar 

  28. DePristo, M.A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).

    Article  CAS  Google Scholar 

  29. Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).

    Article  CAS  Google Scholar 

  30. Robinson, J.T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).

    Article  CAS  Google Scholar 

  31. Lipson, D. et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat. Med. 18, 382–384 (2012).

    Article  CAS  Google Scholar 

  32. Chandarlapaty, S. et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58–71 (2011).

    Article  CAS  Google Scholar 

  33. MacKerell, A.D. et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586–3616 (1998).

    Article  CAS  Google Scholar 

  34. Brooks, B.R. et al. CHARMM: the biomolecular simulation program. J. Comput. Chem. 30, 1545–1614 (2009).

    Article  CAS  Google Scholar 

  35. Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996).

    Article  CAS  Google Scholar 

  36. Phillips, J.C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Sarat Chandarlapaty.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

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)

Source data

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2822

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer