Focal adhesion kinase (FAK) activation by estrogens involves GPER in triple-negative breast cancer cells.
Cell Line, Tumor
Cell Movement
Databases, Genetic
Estrogens
/ metabolism
Female
Focal Adhesion Kinase 1
/ genetics
Focal Adhesions
/ metabolism
Gene Expression Regulation, Neoplastic
Humans
Receptors, Estrogen
/ genetics
Receptors, G-Protein-Coupled
/ genetics
STAT3 Transcription Factor
/ metabolism
Signal Transduction
Survival Rate
Triple Negative Breast Neoplasms
/ genetics
FAK
G-15
GPER
MDA-MB 231
STAT3, STA21
SUM159
TNBC
VS-4718
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
06 Feb 2019
06 Feb 2019
Historique:
received:
15
11
2018
accepted:
27
01
2019
entrez:
8
2
2019
pubmed:
8
2
2019
medline:
4
6
2019
Statut:
epublish
Résumé
Focal adhesion kinase (FAK) is a cytoplasmatic protein tyrosine kinase that associates with both integrins and growth factor receptors toward the adhesion, migration and invasion of cancer cells. The G-protein coupled estrogen receptor (GPER) has been involved in the stimulatory action of estrogens in breast tumor. In this study, we have investigated the engagement of FAK by GPER signaling in triple negative breast cancer (TNBC) cells. Publicly available large-scale database and patient data sets derived from "The Cancer Genome Atlas" (TCGA; www.cbioportal.org ) were used to assess FAK expression in TNBC, non-TNBC tumors and normal breast tissues. MDA-MB 231 and SUM159 TNBC cells were used as model system. The levels of phosphorylated FAK, other transduction mediators and target genes were detected by western blotting analysis. Focal adhesion assay was carried out in order to determine the focal adhesion points and the formation of focal adhesions (FAs). Luciferase assays were performed to evaluate the promoters activity of c-FOS, EGR1 and CTGF upon GPER activation. The mRNA expression of the aforementioned genes was measured by real time-PCR. Boyden chamber and wound healing assays were used in order to evaluate cell migration. The statistical analysis was performed by ANOVA. We first determined by bioinformatic analysis that the mRNA expression levels of the gene encoding FAK, namely PTK2, is higher in TNBC respect to non-TNBC and normal breast tissues. Next, we found that estrogenic GPER signaling triggers Y397 FAK phosphorylation as well as the increase of focal adhesion points (FAs) in TNBC cells. Besides, we ascertained that GPER and FAK activation are involved in the STAT3 nuclear accumulation and gene expression changes. As biological counterpart, we show that FAK inhibition prevents the migration of TNBC cells upon GPER activation. The present data provide novel insights regarding the action of FAK in TNBC. Moreover, on the basis of our findings estrogenic GPER signaling may be considered among the transduction mechanisms engaging FAK toward breast cancer progression.
Sections du résumé
BACKGROUND
BACKGROUND
Focal adhesion kinase (FAK) is a cytoplasmatic protein tyrosine kinase that associates with both integrins and growth factor receptors toward the adhesion, migration and invasion of cancer cells. The G-protein coupled estrogen receptor (GPER) has been involved in the stimulatory action of estrogens in breast tumor. In this study, we have investigated the engagement of FAK by GPER signaling in triple negative breast cancer (TNBC) cells.
METHODS
METHODS
Publicly available large-scale database and patient data sets derived from "The Cancer Genome Atlas" (TCGA; www.cbioportal.org ) were used to assess FAK expression in TNBC, non-TNBC tumors and normal breast tissues. MDA-MB 231 and SUM159 TNBC cells were used as model system. The levels of phosphorylated FAK, other transduction mediators and target genes were detected by western blotting analysis. Focal adhesion assay was carried out in order to determine the focal adhesion points and the formation of focal adhesions (FAs). Luciferase assays were performed to evaluate the promoters activity of c-FOS, EGR1 and CTGF upon GPER activation. The mRNA expression of the aforementioned genes was measured by real time-PCR. Boyden chamber and wound healing assays were used in order to evaluate cell migration. The statistical analysis was performed by ANOVA.
RESULTS
RESULTS
We first determined by bioinformatic analysis that the mRNA expression levels of the gene encoding FAK, namely PTK2, is higher in TNBC respect to non-TNBC and normal breast tissues. Next, we found that estrogenic GPER signaling triggers Y397 FAK phosphorylation as well as the increase of focal adhesion points (FAs) in TNBC cells. Besides, we ascertained that GPER and FAK activation are involved in the STAT3 nuclear accumulation and gene expression changes. As biological counterpart, we show that FAK inhibition prevents the migration of TNBC cells upon GPER activation.
CONCLUSIONS
CONCLUSIONS
The present data provide novel insights regarding the action of FAK in TNBC. Moreover, on the basis of our findings estrogenic GPER signaling may be considered among the transduction mechanisms engaging FAK toward breast cancer progression.
Identifiants
pubmed: 30728047
doi: 10.1186/s13046-019-1056-8
pii: 10.1186/s13046-019-1056-8
pmc: PMC6364402
doi:
Substances chimiques
Estrogens
0
GPER1 protein, human
0
Receptors, Estrogen
0
Receptors, G-Protein-Coupled
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Focal Adhesion Kinase 1
EC 2.7.10.2
PTK2 protein, human
EC 2.7.10.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
58Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : AIRC-IG 21322
Organisme : Fondazione Umberto Veronesi
ID : Post-Doctoral Fellowship 2018
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