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Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas

BACKGROUND: Tamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positiv...

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Autores principales: Folgiero, Valentina, Avetrani, Paolo, Bon, Giulia, Di Carlo, Selene E., Fabi, Alessandra, Nisticò, Cecilia, Vici, Patrizia, Melucci, Elisa, Buglioni, Simonetta, Perracchio, Letizia, Sperduti, Isabella, Rosanò, Laura, Sacchi, Ada, Mottolese, Marcella, Falcioni, Rita
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2220038/
https://www.ncbi.nlm.nih.gov/pubmed/18270579
http://dx.doi.org/10.1371/journal.pone.0001592
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author Folgiero, Valentina
Avetrani, Paolo
Bon, Giulia
Di Carlo, Selene E.
Fabi, Alessandra
Nisticò, Cecilia
Vici, Patrizia
Melucci, Elisa
Buglioni, Simonetta
Perracchio, Letizia
Sperduti, Isabella
Rosanò, Laura
Sacchi, Ada
Mottolese, Marcella
Falcioni, Rita
author_facet Folgiero, Valentina
Avetrani, Paolo
Bon, Giulia
Di Carlo, Selene E.
Fabi, Alessandra
Nisticò, Cecilia
Vici, Patrizia
Melucci, Elisa
Buglioni, Simonetta
Perracchio, Letizia
Sperduti, Isabella
Rosanò, Laura
Sacchi, Ada
Mottolese, Marcella
Falcioni, Rita
author_sort Folgiero, Valentina
collection PubMed
description BACKGROUND: Tamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positive hormonal receptors. However, the mechanisms involved in endocrine resistance are not clear. Laboratory and clinical data now indicate that bi-directional molecular cross-talk between nuclear or membrane ER and growth factor receptor pathways may be involved in endocrine resistance. We recently found a functional interaction between α6β4 integrin and ErbB-3 receptor to maintain the PI3K/Akt survival pathway of mammary tumour cells. We sought to improve understanding of this process in order to provide the involvement of both receptors insight into mechanism of Tamoxifen resistance. METHODS AND FINDINGS: Using human breast cancer cell lines displaying different levels of α6β4 and ErbB-3 receptors and a series of 232 breast cancer biopsies from patients submitted to adjuvant Tamoxifen monotherapy for five years, we evaluated the functional interaction between both receptors in relationship to Tamoxifen responsiveness. In mammary carcinoma cells, we evidenced that the α6β4 integrin strongly influence Akt phosphorylation through ErbB-3 protein regulation. Moreover, the ErbB-3 inactivation inhibits Akt phosphorylation, induces apoptosis and inhibits in vitro invasion favouring Tamoxifen responsiveness. The analysis of human tumors revealed a significant relationship between α6β4 and ErbB-3 in P-Akt-positive and ERβ1-negative breast cancers derived from patients with lower disease free survival. CONCLUSIONS: We provided evidence that a strong relationship occurs between α6β4 and ErbB-3 positivity in ERβ1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in ERβ1-negative breast cancer derived from patients with lower DFS indicating that both receptors are clinically relevant in predicting the response to Tamoxifen.
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spelling pubmed-22200382008-02-13 Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas Folgiero, Valentina Avetrani, Paolo Bon, Giulia Di Carlo, Selene E. Fabi, Alessandra Nisticò, Cecilia Vici, Patrizia Melucci, Elisa Buglioni, Simonetta Perracchio, Letizia Sperduti, Isabella Rosanò, Laura Sacchi, Ada Mottolese, Marcella Falcioni, Rita PLoS One Research Article BACKGROUND: Tamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positive hormonal receptors. However, the mechanisms involved in endocrine resistance are not clear. Laboratory and clinical data now indicate that bi-directional molecular cross-talk between nuclear or membrane ER and growth factor receptor pathways may be involved in endocrine resistance. We recently found a functional interaction between α6β4 integrin and ErbB-3 receptor to maintain the PI3K/Akt survival pathway of mammary tumour cells. We sought to improve understanding of this process in order to provide the involvement of both receptors insight into mechanism of Tamoxifen resistance. METHODS AND FINDINGS: Using human breast cancer cell lines displaying different levels of α6β4 and ErbB-3 receptors and a series of 232 breast cancer biopsies from patients submitted to adjuvant Tamoxifen monotherapy for five years, we evaluated the functional interaction between both receptors in relationship to Tamoxifen responsiveness. In mammary carcinoma cells, we evidenced that the α6β4 integrin strongly influence Akt phosphorylation through ErbB-3 protein regulation. Moreover, the ErbB-3 inactivation inhibits Akt phosphorylation, induces apoptosis and inhibits in vitro invasion favouring Tamoxifen responsiveness. The analysis of human tumors revealed a significant relationship between α6β4 and ErbB-3 in P-Akt-positive and ERβ1-negative breast cancers derived from patients with lower disease free survival. CONCLUSIONS: We provided evidence that a strong relationship occurs between α6β4 and ErbB-3 positivity in ERβ1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in ERβ1-negative breast cancer derived from patients with lower DFS indicating that both receptors are clinically relevant in predicting the response to Tamoxifen. Public Library of Science 2008-02-13 /pmc/articles/PMC2220038/ /pubmed/18270579 http://dx.doi.org/10.1371/journal.pone.0001592 Text en Folgiero et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Folgiero, Valentina
Avetrani, Paolo
Bon, Giulia
Di Carlo, Selene E.
Fabi, Alessandra
Nisticò, Cecilia
Vici, Patrizia
Melucci, Elisa
Buglioni, Simonetta
Perracchio, Letizia
Sperduti, Isabella
Rosanò, Laura
Sacchi, Ada
Mottolese, Marcella
Falcioni, Rita
Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas
title Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas
title_full Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas
title_fullStr Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas
title_full_unstemmed Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas
title_short Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas
title_sort induction of erbb-3 expression by α6β4 integrin contributes to tamoxifen resistance in erβ1-negative breast carcinomas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2220038/
https://www.ncbi.nlm.nih.gov/pubmed/18270579
http://dx.doi.org/10.1371/journal.pone.0001592
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