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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Toy
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Helen
authors.initials: H
authors.lastname: Won
authors.forename: Bradley
authors.initials: B
authors.lastname: Green
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sakr
authors.forename: Marie
authors.initials: M
authors.lastname: Will
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.forename: Kinisha
authors.initials: K
authors.lastname: Gala
authors.forename: Sean
authors.initials: S
authors.lastname: Fanning
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.forename: Tetiana
authors.initials: T
authors.lastname: Taran
authors.forename: Gabriel
authors.initials: G
authors.lastname: Hortobagyi
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Greene
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004965:Estrogen Antagonists / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D020125:Mutation, Missense; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands