Beyond endocrine resistance: estrogen receptor (ESR1) activating mutations mediate chemotherapy resistance through the JNK/c-Jun MDR1 pathway in breast cancer.
Activating mutations
Chemoresistance
JNK inhibitor
JNK/c-Jun signaling pathway
MDR1
Journal
Breast cancer research and treatment
ISSN: 1573-7217
Titre abrégé: Breast Cancer Res Treat
Pays: Netherlands
ID NLM: 8111104
Informations de publication
Date de publication:
29 Oct 2024
29 Oct 2024
Historique:
received:
21
02
2024
accepted:
03
10
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
aheadofprint
Résumé
All patients with metastatic breast cancer (MBC) expressing estrogen receptor-α (ESR1) will eventually develop resistance to endocrine therapies. In up to 40% of patients, this resistance is caused by activating mutations in the ligand-binding domain (LBD) of ESR1. Accumulating clinical evidence indicate adverse outcomes for these patients, beyond that expected by resistance to endocrine therapy. Here we aimed to study the role of ESR1 mutations in conferring chemoresistance in BC cells. MCF-7 cells harboring Y537S and D538G ESR1 mutations (mut-ER) were employed to study the response to chemotherapy drugs, paclitaxel and doxorubicin, using viability and apoptotic assay in vitro, and tumor growth in vivo. JNK/c-Jun/MDR1 pathway was studied using qRT-PCR, western-blot, gene-reporter and ChIP assays. MDR1 expression was analyzed in clinical samples using IHC. Cell harboring ESR1 mutations displayed relative chemoresistance compared to WT-ER, evidenced by higher viability and reduced apoptosis as well as resistance to paclitaxel in vivo. To elucidate the underlying mechanism, MDR1 expression was examined and elevated levels were observed in mut-ER cells, and in clinical BC samples. MDR1 is regulated by the c-Jun pathway, and we showed high correlation between these two genes in BC using TCGA databases. Accordingly, we detected higher JNK/c-Jun expression and activity in ESR1-mutated cells, as well as increased occupancy of c-Jun in MDR1 promoter. Importantly, JNK inhibition decreased MDR1 expression and restored sensitivity to chemotherapy. Taken together, these data indicate that ESR1 mutations confer chemoresistance through activation of the JNK/MDR1 axis. These finding suggest a novel treatment option for BC tumors expressing ESR1 mutations.
Identifiants
pubmed: 39470848
doi: 10.1007/s10549-024-07507-3
pii: 10.1007/s10549-024-07507-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
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