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The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells.
Fanning, Sean W; Jeselsohn, Rinath; Dharmarajan, Venkatasubramanian; Mayne, Christopher G; Karimi, Mostafa; Buchwalter, Gilles; Houtman, René; Toy, Weiyi; Fowler, Colin E; Han, Ross; Lainé, Muriel; Carlson, Kathryn E; Martin, Teresa A; Nowak, Jason; Nwachukwu, Jerome C; Hosfield, David J; Chandarlapaty, Sarat; Tajkhorshid, Emad; Nettles, Kendall W; Griffin, Patrick R; Shen, Yang; Katzenellenbogen, John A; Brown, Myles; Greene, Geoffrey L.
Afiliación
  • Fanning SW; Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
  • Jeselsohn R; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States.
  • Dharmarajan V; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
  • Mayne CG; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States.
  • Karimi M; Department of Biochemistry, College of Medicine, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States.
  • Buchwalter G; Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, Texas, United States.
  • Houtman R; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States.
  • Toy W; PamGene International BV, 's-Hertogenbosch, The Netherlands.
  • Fowler CE; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
  • Han R; Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
  • Lainé M; Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
  • Carlson KE; Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
  • Martin TA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States.
  • Nowak J; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States.
  • Nwachukwu JC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
  • Hosfield DJ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States.
  • Chandarlapaty S; Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
  • Tajkhorshid E; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
  • Nettles KW; Department of Biochemistry, College of Medicine, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States.
  • Griffin PR; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States.
  • Shen Y; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States.
  • Katzenellenbogen JA; Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, Texas, United States.
  • Brown M; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States.
  • Greene GL; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States.
Elife ; 72018 11 29.
Article en En | MEDLINE | ID: mdl-30489256
ABSTRACT
Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA's selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Resistencia a Antineoplásicos / Moduladores Selectivos de los Receptores de Estrógeno / Receptor alfa de Estrógeno / Indoles Límite: Female / Humans Idioma: En Revista: Elife Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Resistencia a Antineoplásicos / Moduladores Selectivos de los Receptores de Estrógeno / Receptor alfa de Estrógeno / Indoles Límite: Female / Humans Idioma: En Revista: Elife Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos