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Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation

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-bind...

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Autores principales: Fanning, Sean W, Mayne, Christopher G, Dharmarajan, Venkatasubramanian, Carlson, Kathryn E, Martin, Teresa A, Novick, Scott J, Toy, Weiyi, Green, Bradley, Panchamukhi, Srinivas, Katzenellenbogen, Benita S, Tajkhorshid, Emad, Griffin, Patrick R, Shen, Yang, Chandarlapaty, Sarat, Katzenellenbogen, John A, Greene, Geoffrey L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821807/
https://www.ncbi.nlm.nih.gov/pubmed/26836308
http://dx.doi.org/10.7554/eLife.12792
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author Fanning, Sean W
Mayne, Christopher G
Dharmarajan, Venkatasubramanian
Carlson, Kathryn E
Martin, Teresa A
Novick, Scott J
Toy, Weiyi
Green, Bradley
Panchamukhi, Srinivas
Katzenellenbogen, Benita S
Tajkhorshid, Emad
Griffin, Patrick R
Shen, Yang
Chandarlapaty, Sarat
Katzenellenbogen, John A
Greene, Geoffrey L
author_facet Fanning, Sean W
Mayne, Christopher G
Dharmarajan, Venkatasubramanian
Carlson, Kathryn E
Martin, Teresa A
Novick, Scott J
Toy, Weiyi
Green, Bradley
Panchamukhi, Srinivas
Katzenellenbogen, Benita S
Tajkhorshid, Emad
Griffin, Patrick R
Shen, Yang
Chandarlapaty, Sarat
Katzenellenbogen, John A
Greene, Geoffrey L
author_sort Fanning, Sean W
collection PubMed
description 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.
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spelling pubmed-48218072016-04-07 Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation Fanning, Sean W Mayne, Christopher G Dharmarajan, Venkatasubramanian Carlson, Kathryn E Martin, Teresa A Novick, Scott J Toy, Weiyi Green, Bradley Panchamukhi, Srinivas Katzenellenbogen, Benita S Tajkhorshid, Emad Griffin, Patrick R Shen, Yang Chandarlapaty, Sarat Katzenellenbogen, John A Greene, Geoffrey L eLife Structural Biology and Molecular Biophysics 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. eLife Sciences Publications, Ltd 2016-02-02 /pmc/articles/PMC4821807/ /pubmed/26836308 http://dx.doi.org/10.7554/eLife.12792 Text en © 2016, Fanning et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Fanning, Sean W
Mayne, Christopher G
Dharmarajan, Venkatasubramanian
Carlson, Kathryn E
Martin, Teresa A
Novick, Scott J
Toy, Weiyi
Green, Bradley
Panchamukhi, Srinivas
Katzenellenbogen, Benita S
Tajkhorshid, Emad
Griffin, Patrick R
Shen, Yang
Chandarlapaty, Sarat
Katzenellenbogen, John A
Greene, Geoffrey L
Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
title Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
title_full Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
title_fullStr Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
title_full_unstemmed Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
title_short Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
title_sort estrogen receptor alpha somatic mutations y537s and d538g confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821807/
https://www.ncbi.nlm.nih.gov/pubmed/26836308
http://dx.doi.org/10.7554/eLife.12792
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