ESR1 ligand-binding domain mutations in hormone-resistant breast cancer Journal Article
| Authors: | Toy, W.; Shen, Y.; Won, H.; Green, B.; Sakr, R. A.; Will, M.; Li, Z.; Gala, K.; Fanning, S.; King, T. A.; Hudis, C.; Chen, D.; Taran, T.; Hortobagyi, G.; Greene, G.; Berger, M.; Baselga, J.; Chandarlapaty, S. |
| Article Title: | 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. © 2013 Nature America, Inc. |
| Keywords: | clinical article; gene mutation; human cell; cancer growth; nonhuman; treatment duration; genetic analysis; protein conformation; mouse; breast cancer; transcription factor gata 3; molecular dynamics; animal experiment; animal model; aromatase inhibitor; cancer hormone therapy; nucleotide sequence; hydrogen bond; gene dosage; breast metastasis; site directed mutagenesis; ligand binding; hormone resistance; estrogen receptor alpha; human; priority journal; article; ligand binding domain |
| Journal Title: | Nature Genetics |
| Volume: | 45 |
| Issue: | 12 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2013-12-01 |
| Start Page: | 1439 |
| End Page: | 1445 |
| Language: | English |
| DOI: | 10.1038/ng.2822 |
| PROVIDER: | scopus |
| PMCID: | PMC3903423 |
| PUBMED: | 24185512 |
| DOI/URL: | |
| Notes: | Cited By (since 1996):1 -- Export Date: 2 January 2014 -- CODEN: NGENE -- Molecular Sequence Numbers: GENBANK: GSE51448; -- Source: Scopus |
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