ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.
ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.
复制标题
DOI：
10.1038/ng.2822
复制
发表时间：
2013-12
期刊：
影响因子：
30.8
通讯作者：
Chandarlapaty, Sarat
中科院分区：
文献类型：
--
作者：
Toy, Weiyi;Shen, Yang;Won, Helen;Green, Bradley;Sakr, Rita A.;Will, Marie;Li, Zhiqiang;Gala, Kinisha;Fanning, Sean;King, Tari A.;Hudis, Clifford;Chen, David;Taran, Tetiana;Hortobagyi, Gabriel;Greene, Geoffrey;Berger, Michael;Baselga, Jose;Chandarlapaty, Sarat
Seventy percent of breast cancers express estrogen receptor (ER) and most of these are sensitive to ER inhibition. However, many such tumors become refractory to inhibition of estrogen action in the metastatic setting for unknown reasons. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER+ breast tumors and identified mutations in the ligand binding domain (LBD) of ESR1 in 14/80 cases. These included highly recurrent mutations p.Tyr537Ser/Asn and p.Asp538Gly. Molecular dynamics simulations suggest the Tyr537Ser and Asp538Gly structures lead to hydrogen bonding of the mutant amino acid with Asp351, thus favoring the receptor’s agonist conformation. 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 have significant therapeutic benefit.
登录
查看更多内容
影响因子：
45.3
作者：
Gutierrez, MC;Detre, S;Dowsett, M
通讯作者：
Dowsett, M
影响因子：
--
作者：
Fan, MY;Park, A;Nephew, KP
通讯作者：
Nephew, KP
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
56.9
作者：
Shang, YF;Brown, M
通讯作者：
Brown, M
影响因子：
46.9
作者：
通讯作者：
--