Cargando…

Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells

INTRODUCTION: Acquired tamoxifen resistance remains the major obstacle to breast cancer endocrine therapy. β1-integrin was identified as one of the target genes of G protein-coupled estrogen receptor (GPER), a novel estrogen receptor recognized as an initiator of tamoxifen resistance. Here, we inves...

Descripción completa

Detalles Bibliográficos
Autores principales: Yuan, Jie, Liu, Manran, Yang, Li, Tu, Gang, Zhu, Qing, Chen, Maoshan, Cheng, Hong, Luo, Haojun, Fu, Weijie, Li, Zhenhua, Yang, Guanglun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453053/
https://www.ncbi.nlm.nih.gov/pubmed/25990368
http://dx.doi.org/10.1186/s13058-015-0579-y
_version_ 1782374406609174528
author Yuan, Jie
Liu, Manran
Yang, Li
Tu, Gang
Zhu, Qing
Chen, Maoshan
Cheng, Hong
Luo, Haojun
Fu, Weijie
Li, Zhenhua
Yang, Guanglun
author_facet Yuan, Jie
Liu, Manran
Yang, Li
Tu, Gang
Zhu, Qing
Chen, Maoshan
Cheng, Hong
Luo, Haojun
Fu, Weijie
Li, Zhenhua
Yang, Guanglun
author_sort Yuan, Jie
collection PubMed
description INTRODUCTION: Acquired tamoxifen resistance remains the major obstacle to breast cancer endocrine therapy. β1-integrin was identified as one of the target genes of G protein-coupled estrogen receptor (GPER), a novel estrogen receptor recognized as an initiator of tamoxifen resistance. Here, we investigated the role of β1-integrin in GPER-mediated tamoxifen resistance in breast cancer. METHODS: The expression of β1-integrin and biomarkers of epithelial-mesenchymal transition were evaluated immunohistochemically in 53 specimens of metastases and paired primary tumors. The function of β1-integrin was investigated in tamoxifen-resistant (MCF-7R) subclones, derived from parental MCF-7 cells, and MCF-7R β1-integrin-silenced subclones in MTT and Transwell assays. Involved signaling pathways were identified using specific inhibitors and Western blotting analysis. RESULTS: GPER, β1-integrin and mesenchymal biomarkers (vimentin and fibronectin) expression in metastases increased compared to the corresponding primary tumors; a close expression pattern of β1-integrin and GPER were in metastases. Increased β1-integrin expression was also confirmed in MCF-7R cells compared with MCF-7 cells. This upregulation of β1-integrin was induced by agonists of GPER and blocked by both antagonist and knockdown of it in MCF-7R cells. Moreover, the epidermal growth factor receptor/extracellular regulated protein kinase (EGFR/ERK) signaling pathway was involved in this transcriptional regulation since specific inhibitors of these kinases also reduced the GPER-induced upregulation of β1-integrin. Interestingly, silencing of β1-integrin partially rescued the sensitivity of MCF-7R cells to tamoxifen and the α5β1-integrin subunit is probably responsible for this phenomenon. Importantly, the cell migration and epithelial-mesenchymal transition induced by cancer-associated fibroblasts, or the product of cancer-associated fibroblasts, fibronectin, were reduced by knockdown of β1-integrin in MCF-7R cells. In addition, the downstream kinases of β1-integrin including focal adhesion kinase, Src and AKT were activated in MCF-7R cells and may be involved in the interaction between cancer cells and cancer-associated fibroblasts. CONCLUSIONS: GPER/EGFR/ERK signaling upregulates β1-integrin expression and activates downstream kinases, which contributes to cancer-associated fibroblast-induced cell migration and epithelial-mesenchymal transition, in MCF-7R cells. GPER probably contributes to tamoxifen resistance via interaction with the tumor microenvironment in a β1-integrin-dependent pattern. Thus, β1-integrin may be a potential target to improve anti-hormone therapy responses in breast cancer patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0579-y) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4453053
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-44530532015-06-04 Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells Yuan, Jie Liu, Manran Yang, Li Tu, Gang Zhu, Qing Chen, Maoshan Cheng, Hong Luo, Haojun Fu, Weijie Li, Zhenhua Yang, Guanglun Breast Cancer Res Research Article INTRODUCTION: Acquired tamoxifen resistance remains the major obstacle to breast cancer endocrine therapy. β1-integrin was identified as one of the target genes of G protein-coupled estrogen receptor (GPER), a novel estrogen receptor recognized as an initiator of tamoxifen resistance. Here, we investigated the role of β1-integrin in GPER-mediated tamoxifen resistance in breast cancer. METHODS: The expression of β1-integrin and biomarkers of epithelial-mesenchymal transition were evaluated immunohistochemically in 53 specimens of metastases and paired primary tumors. The function of β1-integrin was investigated in tamoxifen-resistant (MCF-7R) subclones, derived from parental MCF-7 cells, and MCF-7R β1-integrin-silenced subclones in MTT and Transwell assays. Involved signaling pathways were identified using specific inhibitors and Western blotting analysis. RESULTS: GPER, β1-integrin and mesenchymal biomarkers (vimentin and fibronectin) expression in metastases increased compared to the corresponding primary tumors; a close expression pattern of β1-integrin and GPER were in metastases. Increased β1-integrin expression was also confirmed in MCF-7R cells compared with MCF-7 cells. This upregulation of β1-integrin was induced by agonists of GPER and blocked by both antagonist and knockdown of it in MCF-7R cells. Moreover, the epidermal growth factor receptor/extracellular regulated protein kinase (EGFR/ERK) signaling pathway was involved in this transcriptional regulation since specific inhibitors of these kinases also reduced the GPER-induced upregulation of β1-integrin. Interestingly, silencing of β1-integrin partially rescued the sensitivity of MCF-7R cells to tamoxifen and the α5β1-integrin subunit is probably responsible for this phenomenon. Importantly, the cell migration and epithelial-mesenchymal transition induced by cancer-associated fibroblasts, or the product of cancer-associated fibroblasts, fibronectin, were reduced by knockdown of β1-integrin in MCF-7R cells. In addition, the downstream kinases of β1-integrin including focal adhesion kinase, Src and AKT were activated in MCF-7R cells and may be involved in the interaction between cancer cells and cancer-associated fibroblasts. CONCLUSIONS: GPER/EGFR/ERK signaling upregulates β1-integrin expression and activates downstream kinases, which contributes to cancer-associated fibroblast-induced cell migration and epithelial-mesenchymal transition, in MCF-7R cells. GPER probably contributes to tamoxifen resistance via interaction with the tumor microenvironment in a β1-integrin-dependent pattern. Thus, β1-integrin may be a potential target to improve anti-hormone therapy responses in breast cancer patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0579-y) contains supplementary material, which is available to authorized users. BioMed Central 2015-05-21 2015 /pmc/articles/PMC4453053/ /pubmed/25990368 http://dx.doi.org/10.1186/s13058-015-0579-y Text en © Yuan et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Yuan, Jie
Liu, Manran
Yang, Li
Tu, Gang
Zhu, Qing
Chen, Maoshan
Cheng, Hong
Luo, Haojun
Fu, Weijie
Li, Zhenhua
Yang, Guanglun
Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells
title Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells
title_full Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells
title_fullStr Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells
title_full_unstemmed Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells
title_short Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells
title_sort acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for g protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453053/
https://www.ncbi.nlm.nih.gov/pubmed/25990368
http://dx.doi.org/10.1186/s13058-015-0579-y
work_keys_str_mv AT yuanjie acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT liumanran acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT yangli acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT tugang acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT zhuqing acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT chenmaoshan acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT chenghong acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT luohaojun acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT fuweijie acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT lizhenhua acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell
AT yangguanglun acquisitionofepithelialmesenchymaltransitionphenotypeinthetamoxifenresistantbreastcancercellanewroleforgproteincoupledestrogenreceptorinmediatingtamoxifenresistancethroughcancerassociatedfibroblastderivedfibronectinandb1integrinsignalingpathwayintumorcell