PH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , |
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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Repositório Institucional da UNESP |
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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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1808128523210063872 |