Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional changes during chemoresistance in triple negative breast cancer
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F25%3A00142811" target="_blank" >RIV/00216224:14110/25:00142811 - isvavai.cz</a>
Result on the web
<a href="https://www.nature.com/articles/s41523-025-00782-3" target="_blank" >https://www.nature.com/articles/s41523-025-00782-3</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41523-025-00782-3" target="_blank" >10.1038/s41523-025-00782-3</a>
Alternative languages
Result language
angličtina
Original language name
Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional changes during chemoresistance in triple negative breast cancer
Original language description
Triple Negative Breast Cancer (TNBC) accounts for similar to 20% of all breast cancers and results in thousands of deaths every year. The median survival of TNBC patients sharply declines with the development of chemoresistance and metastatic disease. Although high expression of ETS1 in TNBC has been associated with aggressiveness, the mechanisms of ETS1 in TNBC therapy relapse are poorly understood. Here, we show that ETS1 is responsible for driving acquired drug resistance in the TNBC cell line models resistant to 5'-Fluorouracil and doxorubicin. Protein kinase, DNAPKcs (aka PRKDC) mediated phosphorylation of ETS1 at Serine 251 residue enhances protein stability by preventing ETS1's degradation, thus enhancing ETS1-driven resistance mechanisms. Further, transcriptomic profiling of resistant cells and TNBC patients showed that phosphorylated-ETS1 could activate genes of the E2F, MYC and G2/M pathways, resulting in enhanced DNA synthesis and proliferation, leading to resistance. DNAPKcs inhibitors resulted in ETS1 degradation, inhibition of proliferation gene circuits and subsequent apoptosis in resistant TNBC cells. Phospho-S251 ETS1 and associated ETS1-driven proliferative gene signatures were observed in drug-resistant TNBC patients. Our findings suggest that DNAPKcs-mediated phosphorylation of ETS1 promotes chemoresistance in TNBC patients and can be targeted using DNAPKcs kinase inhibitors.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30204 - Oncology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
NPJ BREAST CANCER
ISSN
2374-4677
e-ISSN
2374-4677
Volume of the periodical
11
Issue of the periodical within the volume
1
Country of publishing house
DE - GERMANY
Number of pages
15
Pages from-to
1-15
UT code for WoS article
001603317100002
EID of the result in the Scopus database
2-s2.0-105019769414