Back to Search
Start Over
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
- Source :
- Breast Cancer Research : BCR
- Publication Year :
- 2015
- Publisher :
- BioMed Central, 2015.
-
Abstract
- 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.
- Subjects :
- Selective Estrogen Receptor Modulators
Epithelial-Mesenchymal Transition
Antineoplastic Agents, Hormonal
Estrogen receptor
Breast Neoplasms
Biology
Cell Line, Tumor
medicine
Humans
Epithelial–mesenchymal transition
skin and connective tissue diseases
Extracellular Signal-Regulated MAP Kinases
Estrogen receptor beta
Uncategorized
Medicine(all)
Tumor microenvironment
Integrin beta1
Fibroblasts
Immunohistochemistry
Fibronectins
ErbB Receptors
Tamoxifen
src-Family Kinases
Receptors, Estrogen
Drug Resistance, Neoplasm
Focal Adhesion Protein-Tyrosine Kinases
Cancer cell
Cancer research
MCF-7 Cells
Female
Signal transduction
GPER
Biomarkers
medicine.drug
Research Article
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1465542X and 14655411
- Volume :
- 17
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Breast Cancer Research : BCR
- Accession number :
- edsair.doi.dedup.....e81d8a9115db330b5993b2273555c973