Estetrol/GPER/SERPINB2 transduction signaling inhibits the motility of triple-negative breast cancer cells.
Humans
Triple Negative Breast Neoplasms
/ pathology
Cell Movement
/ drug effects
Signal Transduction
Cell Line, Tumor
Receptors, G-Protein-Coupled
/ metabolism
Receptors, Estrogen
/ metabolism
Gene Expression Regulation, Neoplastic
Estetrol
/ pharmacology
Female
Plasminogen Activator Inhibitor 2
/ metabolism
Protein Binding
/ drug effects
Neoplasm Invasiveness
Estetrol (E4)
G protein-coupled estrogen receptor (GPER)
SERPINB2
Triple-negative breast cancer (TNBC)
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
13 May 2024
13 May 2024
Historique:
received:
08
04
2024
accepted:
01
05
2024
medline:
14
5
2024
pubmed:
14
5
2024
entrez:
14
5
2024
Statut:
epublish
Résumé
Estetrol (E4) is a natural estrogen produced by the fetal liver during pregnancy. Due to its favorable safety profile, E4 was recently approved as estrogenic component of a new combined oral contraceptive. E4 is a selective ligand of estrogen receptor (ER)α and ERβ, but its binding to the G Protein-Coupled Estrogen Receptor (GPER) has not been described to date. Therefore, we aimed to explore E4 action in GPER-positive Triple-Negative Breast Cancer (TNBC) cells. The potential interaction between E4 and GPER was investigated by molecular modeling and binding assays. The whole transcriptomic modulation triggered by E4 in TNBC cells via GPER was explored through high-throughput RNA sequencing analyses. Gene and protein expression evaluations as well as migration and invasion assays allowed us to explore the involvement of the GPER-mediated induction of the plasminogen activator inhibitor type 2 (SERPINB2) in the biological responses triggered by E4 in TNBC cells. Furthermore, bioinformatics analysis was aimed at recognizing the biological significance of SERPINB2 in ER-negative breast cancer patients. After the molecular characterization of the E4 binding capacity to GPER, RNA-seq analysis revealed that the plasminogen activator inhibitor type 2 (SERPINB2) is one of the most up-regulated genes by E4 in a GPER-dependent manner. Worthy, we demonstrated that the GPER-mediated increase of SERPINB2 is engaged in the anti-migratory and anti-invasive effects elicited by E4 in TNBC cells. In accordance with these findings, a correlation between SERPINB2 levels and a good clinical outcome was found in ER-negative breast cancer patients. Overall, our results provide new insights into the mechanisms through which E4 can halt migratory and invasive features of TNBC cells.
Sections du résumé
BACKGROUND
BACKGROUND
Estetrol (E4) is a natural estrogen produced by the fetal liver during pregnancy. Due to its favorable safety profile, E4 was recently approved as estrogenic component of a new combined oral contraceptive. E4 is a selective ligand of estrogen receptor (ER)α and ERβ, but its binding to the G Protein-Coupled Estrogen Receptor (GPER) has not been described to date. Therefore, we aimed to explore E4 action in GPER-positive Triple-Negative Breast Cancer (TNBC) cells.
METHODS
METHODS
The potential interaction between E4 and GPER was investigated by molecular modeling and binding assays. The whole transcriptomic modulation triggered by E4 in TNBC cells via GPER was explored through high-throughput RNA sequencing analyses. Gene and protein expression evaluations as well as migration and invasion assays allowed us to explore the involvement of the GPER-mediated induction of the plasminogen activator inhibitor type 2 (SERPINB2) in the biological responses triggered by E4 in TNBC cells. Furthermore, bioinformatics analysis was aimed at recognizing the biological significance of SERPINB2 in ER-negative breast cancer patients.
RESULTS
RESULTS
After the molecular characterization of the E4 binding capacity to GPER, RNA-seq analysis revealed that the plasminogen activator inhibitor type 2 (SERPINB2) is one of the most up-regulated genes by E4 in a GPER-dependent manner. Worthy, we demonstrated that the GPER-mediated increase of SERPINB2 is engaged in the anti-migratory and anti-invasive effects elicited by E4 in TNBC cells. In accordance with these findings, a correlation between SERPINB2 levels and a good clinical outcome was found in ER-negative breast cancer patients.
CONCLUSIONS
CONCLUSIONS
Overall, our results provide new insights into the mechanisms through which E4 can halt migratory and invasive features of TNBC cells.
Identifiants
pubmed: 38741146
doi: 10.1186/s12967-024-05269-6
pii: 10.1186/s12967-024-05269-6
doi:
Substances chimiques
Receptors, G-Protein-Coupled
0
Receptors, Estrogen
0
Estetrol
ENB39R14VF
Plasminogen Activator Inhibitor 2
0
GPER1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
450Subventions
Organisme : Mithra Phamraceuticals
ID : Mithra Phamraceuticals
Informations de copyright
© 2024. The Author(s).
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