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Open Access 29-10-2024 | Breast Cancer | Research

Beyond endocrine resistance: estrogen receptor (ESR1) activating mutations mediate chemotherapy resistance through the JNK/c-Jun MDR1 pathway in breast cancer

Authors: Marwa Taya, Keren Merenbakh-Lamin, Asia Zubkov, Zohar Honig, Alina Kurolap, Ori Mayer, Noam Shomron, Ido Wolf, Tami Rubinek

Published in: Breast Cancer Research and Treatment

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Abstract

Purpose

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.

Methods

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.

Results

 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.

Conclusions

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.
Appendix
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Literature
24.
go back to reference Kaemmerer D, Peter L, Lupp A, Schulz S, Sänger J, Baum RP, Prasad V, Hommann M (2012) Comparing of IRS and Her2 as immunohistochemical scoring schemes in gastroenteropancreatic neuroendocrine tumors. Int J Clin Exp Pathol 5(3):187–94PubMedPubMedCentral Kaemmerer D, Peter L, Lupp A, Schulz S, Sänger J, Baum RP, Prasad V, Hommann M (2012) Comparing of IRS and Her2 as immunohistochemical scoring schemes in gastroenteropancreatic neuroendocrine tumors. Int J Clin Exp Pathol 5(3):187–94PubMedPubMedCentral
43.
go back to reference Johnson DE The JNK pathway in drug resistance. In: Targeting Cell Surviv Pathw Enhanc Res Chemother 4:87–100. Johnson DE The JNK pathway in drug resistance. In: Targeting Cell Surviv Pathw Enhanc Res Chemother 4:87–100.
Metadata
Title
Beyond endocrine resistance: estrogen receptor (ESR1) activating mutations mediate chemotherapy resistance through the JNK/c-Jun MDR1 pathway in breast cancer
Authors
Marwa Taya
Keren Merenbakh-Lamin
Asia Zubkov
Zohar Honig
Alina Kurolap
Ori Mayer
Noam Shomron
Ido Wolf
Tami Rubinek
Publication date
29-10-2024
Publisher
Springer US
Published in
Breast Cancer Research and Treatment
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-024-07507-3
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