PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α

Detalhes bibliográficos
Autor(a) principal: De Oliveira, Vinícius M.
Data de Publicação: 2022
Outros Autores: Dias, Marieli M. G., Avelino, Thayná M., Videira, Natália B., Da Silva, Fernando B. [UNESP], Doratioto, Tábata R., Whitford, Paul C., Leite, Vitor B. P. [UNESP], Figueira, Ana Carolina M.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.1021/acs.biochem.1c00806
http://hdl.handle.net/11449/223640
Resumo: Estrogen receptor α (ERα) is a regulatory protein that can access a set of distinct structural configurations. ERα undergoes extensive remodeling as it interacts with different agonists and antagonists, as well as transcription activation and repression factors. Moreover, breast cancer tumors resistant to hormone therapy have been associated with the imbalance between the active and inactive ERα states. Cancer-activating mutations in ERα play a crucial role in this imbalance and can promote the progression of cancer. However, the rate of this progression can also be increased by dysregulated pH in the tumor microenvironment. Many molecular aspects of the process of activation of ERα that can be affected by these pH changes and mutations are still unclear. Thus, we applied computational and experimental techniques to explore the activation process dynamics of ER for environments with different pHs and in the presence of one of the most recurrent cancer-activating mutations, D538G. Our results indicated that the effect of the pH increase associated with the D538G mutation promoted a robust stabilization of the active state of ER. We were also able to determine the main protein regions that have the most potential to influence the activation process under different pH conditions, which may provide targets of future therapeutics for the treatment of hormone-resistant breast cancer tumors. Finally, the approach used here can be applied for proteins associated with the proliferation of other cancer types, which can also have their function affected by small pH changes.
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spelling PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor αEstrogen receptor α (ERα) is a regulatory protein that can access a set of distinct structural configurations. ERα undergoes extensive remodeling as it interacts with different agonists and antagonists, as well as transcription activation and repression factors. Moreover, breast cancer tumors resistant to hormone therapy have been associated with the imbalance between the active and inactive ERα states. Cancer-activating mutations in ERα play a crucial role in this imbalance and can promote the progression of cancer. However, the rate of this progression can also be increased by dysregulated pH in the tumor microenvironment. Many molecular aspects of the process of activation of ERα that can be affected by these pH changes and mutations are still unclear. Thus, we applied computational and experimental techniques to explore the activation process dynamics of ER for environments with different pHs and in the presence of one of the most recurrent cancer-activating mutations, D538G. Our results indicated that the effect of the pH increase associated with the D538G mutation promoted a robust stabilization of the active state of ER. We were also able to determine the main protein regions that have the most potential to influence the activation process under different pH conditions, which may provide targets of future therapeutics for the treatment of hormone-resistant breast cancer tumors. Finally, the approach used here can be applied for proteins associated with the proliferation of other cancer types, which can also have their function affected by small pH changes.Brazilian Biosciences National Laboratory National Center for Research in Energy and Materials LNBio/CNPEM, SPDepartment of Physics São Paulo State University (UNESP) Institute of Biosciences Humanities and Exact Sciences, SPDepartment of Physics Northeastern UniversityDepartment of Physics São Paulo State University (UNESP) Institute of Biosciences Humanities and Exact Sciences, SPLNBio/CNPEMUniversidade Estadual Paulista (UNESP)Northeastern UniversityDe Oliveira, Vinícius M.Dias, Marieli M. G.Avelino, Thayná M.Videira, Natália B.Da Silva, Fernando B. [UNESP]Doratioto, Tábata R.Whitford, Paul C.Leite, Vitor B. P. [UNESP]Figueira, Ana Carolina M.2022-04-28T19:51:55Z2022-04-28T19:51:55Z2022-03-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article455-463http://dx.doi.org/10.1021/acs.biochem.1c00806Biochemistry, v. 61, n. 6, p. 455-463, 2022.1520-49950006-2960http://hdl.handle.net/11449/22364010.1021/acs.biochem.1c008062-s2.0-85126320976Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBiochemistryinfo:eu-repo/semantics/openAccess2022-04-28T19:51:55Zoai:repositorio.unesp.br:11449/223640Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T15:30:19.574708Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α
title PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α
spellingShingle PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α
De Oliveira, Vinícius M.
title_short PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α
title_full PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α
title_fullStr PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α
title_full_unstemmed PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α
title_sort PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α
author De Oliveira, Vinícius M.
author_facet De Oliveira, Vinícius M.
Dias, Marieli M. G.
Avelino, Thayná M.
Videira, Natália B.
Da Silva, Fernando B. [UNESP]
Doratioto, Tábata R.
Whitford, Paul C.
Leite, Vitor B. P. [UNESP]
Figueira, Ana Carolina M.
author_role author
author2 Dias, Marieli M. G.
Avelino, Thayná M.
Videira, Natália B.
Da Silva, Fernando B. [UNESP]
Doratioto, Tábata R.
Whitford, Paul C.
Leite, Vitor B. P. [UNESP]
Figueira, Ana Carolina M.
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv LNBio/CNPEM
Universidade Estadual Paulista (UNESP)
Northeastern University
dc.contributor.author.fl_str_mv De Oliveira, Vinícius M.
Dias, Marieli M. G.
Avelino, Thayná M.
Videira, Natália B.
Da Silva, Fernando B. [UNESP]
Doratioto, Tábata R.
Whitford, Paul C.
Leite, Vitor B. P. [UNESP]
Figueira, Ana Carolina M.
description Estrogen receptor α (ERα) is a regulatory protein that can access a set of distinct structural configurations. ERα undergoes extensive remodeling as it interacts with different agonists and antagonists, as well as transcription activation and repression factors. Moreover, breast cancer tumors resistant to hormone therapy have been associated with the imbalance between the active and inactive ERα states. Cancer-activating mutations in ERα play a crucial role in this imbalance and can promote the progression of cancer. However, the rate of this progression can also be increased by dysregulated pH in the tumor microenvironment. Many molecular aspects of the process of activation of ERα that can be affected by these pH changes and mutations are still unclear. Thus, we applied computational and experimental techniques to explore the activation process dynamics of ER for environments with different pHs and in the presence of one of the most recurrent cancer-activating mutations, D538G. Our results indicated that the effect of the pH increase associated with the D538G mutation promoted a robust stabilization of the active state of ER. We were also able to determine the main protein regions that have the most potential to influence the activation process under different pH conditions, which may provide targets of future therapeutics for the treatment of hormone-resistant breast cancer tumors. Finally, the approach used here can be applied for proteins associated with the proliferation of other cancer types, which can also have their function affected by small pH changes.
publishDate 2022
dc.date.none.fl_str_mv 2022-04-28T19:51:55Z
2022-04-28T19:51:55Z
2022-03-15
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.1021/acs.biochem.1c00806
Biochemistry, v. 61, n. 6, p. 455-463, 2022.
1520-4995
0006-2960
http://hdl.handle.net/11449/223640
10.1021/acs.biochem.1c00806
2-s2.0-85126320976
url http://dx.doi.org/10.1021/acs.biochem.1c00806
http://hdl.handle.net/11449/223640
identifier_str_mv Biochemistry, v. 61, n. 6, p. 455-463, 2022.
1520-4995
0006-2960
10.1021/acs.biochem.1c00806
2-s2.0-85126320976
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Biochemistry
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 455-463
dc.source.none.fl_str_mv Scopus
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
repository.mail.fl_str_mv
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