ESR1 ligand binding domain mutations in hormone-resistant breast cancer
By Weiyi Toy, Yang Shen, H. Won, B. Green, R. Sakr, Marie Will, Zhiqiang Li, Kinisha Gala, S. Fanning, T. King and 8 more. Nature Genetics, 2013
1,143 citations recorded by the source corpus.
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.
Subfields: Computational Theory and Mathematics, Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/b8a6276560d63c294603fb943779db6b03696fa7
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Citations in the corpus
- Signal transduction in cancer. (2015, neutral): “Disruption of the balance between ERa and ERb or mutations in ERa that yield truncated proteins or activated proteins can dysregulate this pathway (Thomas and Gustafsson 2011; Li et al. 2013; Robinson et al. 2013; Toy et al. 2013).”
- Overcoming Endocrine Resistance in Breast Cancer (2020, positive): “Stable ESR1 in-frame gene fusions were first reported in 2013 (Li et al., 2013) and have since been found in at least 1% of MBCs (usually in tumors resistant to endocrine therapy) (Hartmaier et al., 2018), although the frequency is likely higher considering capture-based targeted exon sequencing oft”
- Genomic Evolution of Breast Cancer Metastasis and Relapse (2017, background): “As previously reported, ESR1 resistancemutations were found in five patients previously treated with endocrine therapies (Chandarlapaty et al., 2016; Robinson et al., 2013; Toy et al., 2013) and predicted progressive disease upon switching treatment (Figure S5).”
- The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers (2018, background): “Recently, ligand binding domain mutations in the estrogen receptor (ER) gene (ESR1) were shown to be present in 18% of endocrineresistant HR breast cancers (Schiavon et al., 2015; Toy et al., 2013).”
- Multiscale Embedded Gene Co-expression Network Analysis (2015, background): “For instance, AR and ESR1 are well-established endocrine receptors in breast cancer [46, 47].”