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Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer

Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-A...

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Autores principales: Montoya, Alexa, Amaya, Clarissa N., Belmont, Andres, Diab, Nabih, Trevino, Richard, Villanueva, Geri, Rains, Steven, Sanchez, Luis A., Badri, Nabeel, Otoukesh, Salman, Khammanivong, Ali, Liss, Danielle, Baca, Sarah T., Aguilera, Renato J., Dickerson, Erin B., Torabi, Alireza, Dwivedi, Alok K., Abbas, Aamer, Chambers, Karinn, Bryan, Brad A., Nahleh, Zeina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351644/
https://www.ncbi.nlm.nih.gov/pubmed/28031536
http://dx.doi.org/10.18632/oncotarget.14119
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author Montoya, Alexa
Amaya, Clarissa N.
Belmont, Andres
Diab, Nabih
Trevino, Richard
Villanueva, Geri
Rains, Steven
Sanchez, Luis A.
Badri, Nabeel
Otoukesh, Salman
Khammanivong, Ali
Liss, Danielle
Baca, Sarah T.
Aguilera, Renato J.
Dickerson, Erin B.
Torabi, Alireza
Dwivedi, Alok K.
Abbas, Aamer
Chambers, Karinn
Bryan, Brad A.
Nahleh, Zeina
author_facet Montoya, Alexa
Amaya, Clarissa N.
Belmont, Andres
Diab, Nabih
Trevino, Richard
Villanueva, Geri
Rains, Steven
Sanchez, Luis A.
Badri, Nabeel
Otoukesh, Salman
Khammanivong, Ali
Liss, Danielle
Baca, Sarah T.
Aguilera, Renato J.
Dickerson, Erin B.
Torabi, Alireza
Dwivedi, Alok K.
Abbas, Aamer
Chambers, Karinn
Bryan, Brad A.
Nahleh, Zeina
author_sort Montoya, Alexa
collection PubMed
description Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation.
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spelling pubmed-53516442017-04-13 Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer Montoya, Alexa Amaya, Clarissa N. Belmont, Andres Diab, Nabih Trevino, Richard Villanueva, Geri Rains, Steven Sanchez, Luis A. Badri, Nabeel Otoukesh, Salman Khammanivong, Ali Liss, Danielle Baca, Sarah T. Aguilera, Renato J. Dickerson, Erin B. Torabi, Alireza Dwivedi, Alok K. Abbas, Aamer Chambers, Karinn Bryan, Brad A. Nahleh, Zeina Oncotarget Research Paper Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation. Impact Journals LLC 2016-12-23 /pmc/articles/PMC5351644/ /pubmed/28031536 http://dx.doi.org/10.18632/oncotarget.14119 Text en Copyright: © 2017 Montoya et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Montoya, Alexa
Amaya, Clarissa N.
Belmont, Andres
Diab, Nabih
Trevino, Richard
Villanueva, Geri
Rains, Steven
Sanchez, Luis A.
Badri, Nabeel
Otoukesh, Salman
Khammanivong, Ali
Liss, Danielle
Baca, Sarah T.
Aguilera, Renato J.
Dickerson, Erin B.
Torabi, Alireza
Dwivedi, Alok K.
Abbas, Aamer
Chambers, Karinn
Bryan, Brad A.
Nahleh, Zeina
Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer
title Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer
title_full Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer
title_fullStr Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer
title_full_unstemmed Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer
title_short Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer
title_sort use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351644/
https://www.ncbi.nlm.nih.gov/pubmed/28031536
http://dx.doi.org/10.18632/oncotarget.14119
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