Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782425639925579776 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4821807 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT fanningseanw estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT maynechristopherg estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT dharmarajanvenkatasubramanian estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT carlsonkathryne estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT martinteresaa estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT novickscottj estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT toyweiyi estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT greenbradley estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT panchamukhisrinivas estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT katzenellenbogenbenitas estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT tajkhorshidemad estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT griffinpatrickr estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT shenyang estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT chandarlapatysarat estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT katzenellenbogenjohna estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation AT greenegeoffreyl estrogenreceptoralphasomaticmutationsy537sandd538gconferbreastcancerendocrineresistancebystabilizingtheactivatingfunction2bindingconformation |