Acquisition of Letrozole Resistance Through Activation of the p38/MAPK Signaling Cascade.
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Aromatase Inhibitors
/ pharmacology
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Resistance, Neoplasm
Female
Humans
Letrozole
/ pharmacology
Proteomics
Signal Transduction
p38 Mitogen-Activated Protein Kinases
/ metabolism
Breast cancer
and MAPK
aromatase inhibitor
letrozole
p38
resistance
Journal
Anticancer research
ISSN: 1791-7530
Titre abrégé: Anticancer Res
Pays: Greece
ID NLM: 8102988
Informations de publication
Date de publication:
Feb 2021
Feb 2021
Historique:
received:
30
11
2020
revised:
31
12
2020
accepted:
04
01
2021
entrez:
31
1
2021
pubmed:
1
2
2021
medline:
9
2
2021
Statut:
ppublish
Résumé
Previous reports identified a global proteomic signature of estrogen-independent letrozole resistant breast cancer cells, however, it remains unclear how letrozole-resistance is impacted when cells remain estrogen receptor positive (ER+). To capture the protein expression profile associated with ER+ Aromatase inhibitor (AI) resistance, a global proteomic analysis was conducted using the letrozole-sensitive (T47Darom cells) and letrozole-resistant cells (T47DaromLR cells). To examine the molecular features associated with this phenotype Kaplan- Meier analysis, phospho-antibody arrays, proliferation and apoptosis assays were conducted. MAP3K6 was up-regulated in the T47DaromLR cells by 3.2-fold (p<0.01) which was associated with a decrease in relapse-free survival among breast cancer patients (p=0.0019). Members of the MAPK/p38 pathway (i.e., phospho-MKK6, phospho-p38, phospho-RSK1, phospho-RSK2, and p70S6K MAPK) were also increased in the T47DaromLR cells, while inhibiting p38 led to decreased proliferation and induction of apoptosis. Activation of the p38/MAPK pathway leads to ER+ AI-resistance.
Sections du résumé
BACKGROUND/AIM
OBJECTIVE
Previous reports identified a global proteomic signature of estrogen-independent letrozole resistant breast cancer cells, however, it remains unclear how letrozole-resistance is impacted when cells remain estrogen receptor positive (ER+).
MATERIALS AND METHODS
METHODS
To capture the protein expression profile associated with ER+ Aromatase inhibitor (AI) resistance, a global proteomic analysis was conducted using the letrozole-sensitive (T47Darom cells) and letrozole-resistant cells (T47DaromLR cells). To examine the molecular features associated with this phenotype Kaplan- Meier analysis, phospho-antibody arrays, proliferation and apoptosis assays were conducted.
RESULTS
RESULTS
MAP3K6 was up-regulated in the T47DaromLR cells by 3.2-fold (p<0.01) which was associated with a decrease in relapse-free survival among breast cancer patients (p=0.0019). Members of the MAPK/p38 pathway (i.e., phospho-MKK6, phospho-p38, phospho-RSK1, phospho-RSK2, and p70S6K MAPK) were also increased in the T47DaromLR cells, while inhibiting p38 led to decreased proliferation and induction of apoptosis.
CONCLUSION
CONCLUSIONS
Activation of the p38/MAPK pathway leads to ER+ AI-resistance.
Identifiants
pubmed: 33517263
pii: 41/2/583
doi: 10.21873/anticanres.14810
pmc: PMC8556662
mid: NIHMS1748519
doi:
Substances chimiques
Antineoplastic Agents
0
Aromatase Inhibitors
0
Letrozole
7LKK855W8I
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
583-599Subventions
Organisme : NIGMS NIH HHS
ID : R43 GM126617
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD007582
Pays : United States
Organisme : NIMHD NIH HHS
ID : G12 MD007595
Pays : United States
Organisme : NIMHD NIH HHS
ID : G12 MD007582
Pays : United States
Organisme : NIGMS NIH HHS
ID : SC1 GM125617
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD007595
Pays : United States
Organisme : NIGMS NIH HHS
ID : R44 GM126617
Pays : United States
Informations de copyright
Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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