ESR1 ligand-binding domain mutations in hormone-resistant breast cancer
Weiyi Toy, Yang Shen, Helen Won, Bradley Green, Rita A Sakr, Marie Will, Zhiqiang Li, Kinisha Gala, Sean Fanning, Tari A King, Clifford Hudis, David Chen, Tetiana Taran, Gabriel Hortobagyi, Geoffrey Greene, Michael Berger, José Baselga, Sarat Chandarlapaty, Weiyi Toy, Yang Shen, Helen Won, Bradley Green, Rita A Sakr, Marie Will, Zhiqiang Li, Kinisha Gala, Sean Fanning, Tari A King, Clifford Hudis, David Chen, Tetiana Taran, Gabriel Hortobagyi, Geoffrey Greene, Michael Berger, José Baselga, Sarat Chandarlapaty
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.
Conflict of interest statement
Competing Financial interests
The authors declare no competing financial interests.
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References
- Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717.
- Ariazi EA, Ariazi JL, Cordera F, Jordan VC. Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem. 2006;6:181–202.
- Strasser-Weippl K, Goss PE. Advances in adjuvant hormonal therapy for postmenopausal women. J Clin Oncol. 2005;23:1751–9.
- Forbes JF, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008;9:45–53.
- Peng J, Sengupta S, Jordan VC. Potential of selective estrogen receptor modulators as treatments and preventives of breast cancer. Anticancer Agents Med Chem. 2009;9:481–99.
- Wagle N, et al. High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discov. 2012;2:82–93.
- Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.
- Gutierrez MC, et al. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol. 2005;23:2469–76.
- 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. 2005;104:257–63.
- Meng S, et al. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A. 2004;101:9393–8.
- Jirstrom K, et al. Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res. 2005;65:8009–16.
- Turner N, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70:2085–94.
- Baselga J, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9.
- Nettles KW, et al. NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nat Chem Biol. 2008;4:241–7.
- Zhang QX, Borg A, Wolf DM, Oesterreich S, Fuqua SA. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997;57:1244–9.
- Kato S, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995;270:1491–4.
- Le Goff P, Montano MM, Schodin DJ, Katzenellenbogen BS. Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. J Biol Chem. 1994;269:4458–66.
- Anzick SL, et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science. 1997;277:965–8.
- Azorsa DO, Cunliffe HE, Meltzer PS. Association of steroid receptor coactivator AIB1 with estrogen receptor-alpha in breast cancer cells. Breast Cancer Res Treat. 2001;70:89–101.
- Fan M, Park A, Nephew KP. CHIP (carboxyl terminus of Hsc70-interacting protein) promotes basal and geldanamycin-induced degradation of estrogen receptor-alpha. Mol Endocrinol. 2005;19:2901–14.
- Chandarlapaty S, et al. SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin Cancer Res. 2008;14:240–8.
- Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science. 2002;295:2465–8.
- Weis KE, Ekena K, Thomas JA, Lazennec G, Katzenellenbogen BS. Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. Mol Endocrinol. 1996;10:1388–98.
- Brzozowski AM, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997;389:753–8.
- Won H, SS Detecting Somatic Genetic Alterations in Tumor Specimens by Exon Capture and Massively Parallel Sequencing. Journal of Visualized Experiments. 2013
- Li H, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.
- Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.
- DePristo MA, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491–8.
- Robinson JT, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.
- Lipson D, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18:382–4.
- Chandarlapaty S, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19:58–71.
- MacKerell AD, Bashford JD, Dunbrack M, Evanseck RL, Jr, Field JD, Fischer MJ, Gao S, Guo J, Ha H, Joseph-McCarthy S, Kuchnir DL, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE, III, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D, Karplus M. All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins. J Phys Chem B. 1998;102:3586–3616.
- Brooks BR, et al. CHARMM: the biomolecular simulation program. J Comput Chem. 2009;30:1545–614.
- Phillips JC, et al. Scalable molecular dynamics with NAMD. J Comput Chem. 2005;26:1781–802.
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