title: Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation.
abstract: Somatic mutations in the estrogen receptor alpha (ERα) gene (ESR1), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell-based studies demonstrated that these mutants confer ERα constitutive activity and antiestrogen resistance and suggest that ligand-binding domain dysfunction leads to endocrine therapy resistance. Here, we integrate biophysical and structural biology data to reveal how these mutations lead to a constitutively active and antiestrogen-resistant ERα. We show that these mutant ERs recruit coactivator in the absence of hormone while their affinities for estrogen agonist (estradiol) and antagonist (4-hydroxytamoxifen) are reduced. Further, they confer antiestrogen resistance by altering the conformational dynamics of the loop connecting Helix 11 and Helix 12 in the ligand-binding domain of ERα, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
authors.forename: Sean W
authors.identifier: http://orcid.org/0000-0002-9428-0060
authors.initials: SW
authors.lastname: Fanning
authors.affiliation: Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, United States.|Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States.|Department of Biochemistry, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States.
authors.forename: Christopher G
authors.identifier: http://orcid.org/0000-0001-8905-6569
authors.initials: CG
authors.lastname: Mayne
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States.
authors.forename: Venkatasubramanian
authors.initials: V
authors.lastname: Dharmarajan
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Martin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Novick
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Toy
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
authors.forename: Bradley
authors.identifier: http://orcid.org/0000-0003-4106-285X
authors.initials: B
authors.lastname: Green
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Panchamukhi
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, United States.
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.affiliation: Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, United States.|Department of Biochemistry, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States.
authors.forename: Emad
authors.identifier: http://orcid.org/0000-0001-8434-1010
authors.initials: E
authors.lastname: Tajkhorshid
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, College Station, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, United States.
authors.forename: Geoffrey L
authors.identifier: http://orcid.org/0000-0001-6894-8728
authors.initials: GL
authors.lastname: Greene
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D050505:Mutant Proteins
keywords: acquired drug resistance; biophysics; breast cancer; estrogen receptor alpha; hormone; human; human biology; medicine; selective estrogen receptor modulators; somatic mutation; structural biology
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