Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.

<h4>Background</h4>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 pa...

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Main Authors: Valentina Folgiero, Paolo Avetrani, Giulia Bon, Selene E Di Carlo, Alessandra Fabi, Cecilia Nisticò, Patrizia Vici, Elisa Melucci, Simonetta Buglioni, Letizia Perracchio, Isabella Sperduti, Laura Rosanò, Ada Sacchi, Marcella Mottolese, Rita Falcioni
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2008-02-01
Series:PLoS ONE
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18270579/?tool=EBI
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spelling doaj-66d59f94593e4c78821476da0f2174ef2021-03-03T22:25:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-02-0132e159210.1371/journal.pone.0001592Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.Valentina FolgieroPaolo AvetraniGiulia BonSelene E Di CarloAlessandra FabiCecilia NisticòPatrizia ViciElisa MelucciSimonetta BuglioniLetizia PerracchioIsabella SperdutiLaura RosanòAda SacchiMarcella MottoleseRita Falcioni<h4>Background</h4>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 alpha6beta4 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.<h4>Methods and findings</h4>Using human breast cancer cell lines displaying different levels of alpha6beta4 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 alpha6beta4 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 alpha6beta4 and ErbB-3 in P-Akt-positive and ERbeta1-negative breast cancers derived from patients with lower disease free survival.<h4>Conclusions</h4>We provided evidence that a strong relationship occurs between alpha6beta4 and ErbB-3 positivity in ERbeta1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in ERbeta1-negative breast cancer derived from patients with lower DFS indicating that both receptors are clinically relevant in predicting the response to Tamoxifen.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18270579/?tool=EBI
collection DOAJ
language English
format Article
sources DOAJ
author Valentina Folgiero
Paolo Avetrani
Giulia Bon
Selene E Di Carlo
Alessandra Fabi
Cecilia Nisticò
Patrizia Vici
Elisa Melucci
Simonetta Buglioni
Letizia Perracchio
Isabella Sperduti
Laura Rosanò
Ada Sacchi
Marcella Mottolese
Rita Falcioni
spellingShingle Valentina Folgiero
Paolo Avetrani
Giulia Bon
Selene E Di Carlo
Alessandra Fabi
Cecilia Nisticò
Patrizia Vici
Elisa Melucci
Simonetta Buglioni
Letizia Perracchio
Isabella Sperduti
Laura Rosanò
Ada Sacchi
Marcella Mottolese
Rita Falcioni
Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.
PLoS ONE
author_facet Valentina Folgiero
Paolo Avetrani
Giulia Bon
Selene E Di Carlo
Alessandra Fabi
Cecilia Nisticò
Patrizia Vici
Elisa Melucci
Simonetta Buglioni
Letizia Perracchio
Isabella Sperduti
Laura Rosanò
Ada Sacchi
Marcella Mottolese
Rita Falcioni
author_sort Valentina Folgiero
title Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.
title_short Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.
title_full Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.
title_fullStr Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.
title_full_unstemmed Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.
title_sort induction of erbb-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in erbeta1-negative breast carcinomas.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2008-02-01
description <h4>Background</h4>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 alpha6beta4 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.<h4>Methods and findings</h4>Using human breast cancer cell lines displaying different levels of alpha6beta4 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 alpha6beta4 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 alpha6beta4 and ErbB-3 in P-Akt-positive and ERbeta1-negative breast cancers derived from patients with lower disease free survival.<h4>Conclusions</h4>We provided evidence that a strong relationship occurs between alpha6beta4 and ErbB-3 positivity in ERbeta1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in ERbeta1-negative breast cancer derived from patients with lower DFS indicating that both receptors are clinically relevant in predicting the response to Tamoxifen.
url https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18270579/?tool=EBI
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