Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional
changes during chemoresistance in triple negative breast cancer

J 2025

Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional changes during chemoresistance in triple negative breast cancer

DHARA, Aiindrila; Imlimaong AIER; Souhadri DAS; Manash SARKAR; Ramandeep KAUR et al.

Základní údaje

Originální název

Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional changes during chemoresistance in triple negative breast cancer

Autoři

DHARA, Aiindrila; Imlimaong AIER; Souhadri DAS; Manash SARKAR; Ramandeep KAUR; Pritish Kumar VARADWAJ; Samrat DARIPA; Sumit Kumar HIRA; Anindya HALDER a Nirmalya SEN

Vydání

NPJ BREAST CANCER, BERLIN, NATURE PORTFOLIO, 2025, 2374-4677

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 7.600 v roce 2024

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/25:00142811

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

ETS1; DNA-PKcs; chemoresistance; triple-negative breast cancer; transcriptional regulation

Štítky

14110323, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 4. 12. 2025 13:04, Mgr. Tereza Miškechová

Anotace

V originále

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.

Citovat

DHARA, Aiindrila; Imlimaong AIER; Souhadri DAS; Manash SARKAR; Ramandeep KAUR; Pritish Kumar VARADWAJ; Samrat DARIPA; Sumit Kumar HIRA; Anindya HALDER a Nirmalya SEN. Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional changes during chemoresistance in triple negative breast cancer. NPJ BREAST CANCER. BERLIN: NATURE PORTFOLIO, 2025, roč. 11, č. 1, s. 1-15. ISSN 2374-4677. Dostupné z: https://doi.org/10.1038/s41523-025-00782-3.

@article{2537906,
   author = {Dhara, Aiindrila and Aier, Imlimaong and Das, Souhadri and Sarkar, Manash and Kaur, Ramandeep and Varadwaj, Pritish Kumar and Daripa, Samrat and Hira, Sumit Kumar and Halder, Anindya and Sen, Nirmalya},
   article_location = {BERLIN},
   article_number = {1},
   doi = {https://doi.org/10.1038/s41523-025-00782-3},
   keywords = {ETS1; DNA-PKcs; chemoresistance; triple-negative breast cancer; transcriptional regulation},
   language = {eng},
   issn = {2374-4677},
   journal = {NPJ BREAST CANCER},
   title = {Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional changes during chemoresistance in triple negative breast cancer},
   url = {https://www.nature.com/articles/s41523-025-00782-3},
   volume = {11},
   year = {2025}
}

TY  - JOUR
ID  - 2537906
AU  - Dhara, Aiindrila - Aier, Imlimaong - Das, Souhadri - Sarkar, Manash - Kaur, Ramandeep - Varadwaj, Pritish Kumar - Daripa, Samrat - Hira, Sumit Kumar - Halder, Anindya - Sen, Nirmalya
PY  - 2025
TI  - Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional changes during chemoresistance in triple negative breast cancer
JF  - NPJ BREAST CANCER
VL  - 11
IS  - 1
SP  - 1-15
EP  - 1-15
PB  - NATURE PORTFOLIO
SN  - 23744677
KW  - ETS1
KW  - DNA-PKcs
KW  - chemoresistance
KW  - triple-negative breast cancer
KW  - transcriptional regulation
UR  - https://www.nature.com/articles/s41523-025-00782-3
N2  - 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.
ER  -

DHARA, Aiindrila; Imlimaong AIER; Souhadri DAS; Manash SARKAR; Ramandeep KAUR; Pritish Kumar VARADWAJ; Samrat DARIPA; Sumit Kumar HIRA; Anindya HALDER a Nirmalya SEN. Enhanced ETS1 stability by DNAPKcs orchestrates transcriptional changes during chemoresistance in triple negative breast cancer. \textit{NPJ BREAST CANCER}. BERLIN: NATURE PORTFOLIO, 2025, roč.~11, č.~1, s.~1-15. ISSN~2374-4677. Dostupné z: https://doi.org/10.1038/s41523-025-00782-3.

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