Induction of ErbB-3 expression by α6β4 integrin contributes to tamoxifen resistance in ERβ-1-negative breast carcinomas

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

Research output: Contribution to journalArticle

Abstract

Background: Timoxifen is still the most 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 monoherapy 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 cancer derived from patients with lower disease free survival. Conclusions: We provided evidence that a strong relationship occurs between α6β4 and ErbB-3 posivity 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.

Original languageEnglish
Article numbere1592
JournalPLoS One
Volume3
Issue number2
DOIs
Publication statusPublished - Feb 13 2008

Fingerprint

tamoxifen
integrins
ErbB-3 Receptor
Tamoxifen
Integrins
breast neoplasms
Breast Neoplasms
Phosphorylation
Cells
receptors
Tumors
adjuvants
phosphorylation
Growth Factor Receptors
Biopsy
Phosphatidylinositol 3-Kinases
mammary neoplasms (animal)
phosphatidylinositol 3-kinase
Association reactions
Hormones

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Induction of ErbB-3 expression by α6β4 integrin contributes to tamoxifen resistance in ERβ-1-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.

In: PLoS One, Vol. 3, No. 2, e1592, 13.02.2008.

Research output: Contribution to journalArticle

Folgiero, V, Avetrani, P, Bon, G, Di Carlo, SE, Fabi, A, Nisticò, C, Vici, P, Melucci, E, Buglioni, S, Perracchio, L, Sperduti, I, Rosanò, L, Sacchi, A, Mottolese, M & Falcioni, R 2008, 'Induction of ErbB-3 expression by α6β4 integrin contributes to tamoxifen resistance in ERβ-1-negative breast carcinomas', PLoS One, vol. 3, no. 2, e1592. https://doi.org/10.1371/journal.pone.0001592
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 ERβ-1-negative breast carcinomas. In: PLoS One. 2008 ; Vol. 3, No. 2.
@article{4ccc327c7c844e33ab966b5286f99b23,
title = "Induction of ErbB-3 expression by α6β4 integrin contributes to tamoxifen resistance in ERβ-1-negative breast carcinomas",
abstract = "Background: Timoxifen is still the most 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 monoherapy 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 cancer derived from patients with lower disease free survival. Conclusions: We provided evidence that a strong relationship occurs between α6β4 and ErbB-3 posivity 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.",
author = "Valentina Folgiero and Paolo Avetrani and Giulia Bon and {Di Carlo}, {Selene E.} and Alessandra Fabi and Cecilia Nistic{\`o} and Patrizia Vici and Elisa Melucci and Simonetta Buglioni and Letizia Perracchio and Isabella Sperduti and Laura Rosan{\`o} and Ada Sacchi and Marcella Mottolese and Rita Falcioni",
year = "2008",
month = "2",
day = "13",
doi = "10.1371/journal.pone.0001592",
language = "English",
volume = "3",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - Induction of ErbB-3 expression by α6β4 integrin contributes to tamoxifen resistance in ERβ-1-negative breast carcinomas

AU - Folgiero, Valentina

AU - Avetrani, Paolo

AU - Bon, Giulia

AU - Di Carlo, Selene E.

AU - Fabi, Alessandra

AU - Nisticò, Cecilia

AU - Vici, Patrizia

AU - Melucci, Elisa

AU - Buglioni, Simonetta

AU - Perracchio, Letizia

AU - Sperduti, Isabella

AU - Rosanò, Laura

AU - Sacchi, Ada

AU - Mottolese, Marcella

AU - Falcioni, Rita

PY - 2008/2/13

Y1 - 2008/2/13

N2 - Background: Timoxifen is still the most 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 monoherapy 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 cancer derived from patients with lower disease free survival. Conclusions: We provided evidence that a strong relationship occurs between α6β4 and ErbB-3 posivity 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.

AB - Background: Timoxifen is still the most 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 monoherapy 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 cancer derived from patients with lower disease free survival. Conclusions: We provided evidence that a strong relationship occurs between α6β4 and ErbB-3 posivity 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.

UR - http://www.scopus.com/inward/record.url?scp=45449098301&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=45449098301&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0001592

DO - 10.1371/journal.pone.0001592

M3 - Article

C2 - 18270579

AN - SCOPUS:45449098301

VL - 3

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e1592

ER -