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

被引:871
|
作者
Toy, Weiyi [1 ]
Shen, Yang [2 ]
Won, Helen [1 ]
Green, Bradley [3 ]
Sakr, Rita A. [4 ]
Will, Marie [5 ]
Li, Zhiqiang [1 ]
Gala, Kinisha [1 ]
Fanning, Sean [3 ]
King, Tari A. [4 ]
Hudis, Clifford [5 ,6 ]
Chen, David [7 ]
Taran, Tetiana [7 ]
Hortobagyi, Gabriel [8 ]
Greene, Geoffrey [3 ]
Berger, Michael [1 ,9 ]
Baselga, Jose [1 ,5 ]
Chandarlapaty, Sarat [1 ,5 ,6 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA
[2] Toyota Technol Inst Chicago, Chicago, IL USA
[3] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA
[4] Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10021 USA
[5] Weill Cornell Med Coll, New York, NY USA
[6] Mem Sloan Kettering Canc Ctr, Dept Med, Solid Tumor Div, Breast Canc Med Serv, New York, NY 10021 USA
[7] Novartis Pharmaceut, E Hanover, NJ USA
[8] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA
[9] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA
关键词
ESTROGEN-RECEPTOR; PHOSPHORYLATION; IDENTIFICATION; AMPLIFICATION; TAMOXIFEN; DYNAMICS; THERAPY; HER-2; AIB1;
D O I
10.1038/ng.2822
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:1439 / U189
页数:9
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