Depletion of DNA damage binding protein 2 sensitizes triple‐negative breast cancer cells to poly ADP‐ribose polymerase inhibition by destabilizing Rad51

Poly ADP‐ribose polymerase inhibitors (PARPi) have shown promising therapeutic efficacy in triple‐negative breast cancer (TNBC) patients. However, resistance ultimately develops, preventing a curative effect from being attained. Extensive investigations have indicated the diversity in the mechanisms...

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Bibliographic Details
Published in:Cancer science 2019-11, Vol.110 (11), p.3543-3552
Main Authors: Zhao, Lin, Si, Cheng‐Shuai, Yu, Yue, Lu, Jian‐Wei, Zhuang, Yan
Format: Article
Language:English
Subjects:
Antibiotics
Apoptosis
Biotechnology
Breast cancer
Cancer therapies
Cell Line, Tumor
DDB2
Deoxyribonucleic acid
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA Repair
DNA-Binding Proteins - deficiency
DNA-Binding Proteins - metabolism
Drug Resistance, Neoplasm
Female
Homologous recombination
Humans
Kinases
Lung cancer
Medical prognosis
Metastasis
Neoplasm Proteins - metabolism
Original
Ovarian cancer
PARPi sensitivity
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Proteasomes
Rad51
Rad51 Recombinase - metabolism
Recombinational DNA Repair
Ribose
Therapeutic applications
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - metabolism
triple‐negative breast cancer
Ubiquitination
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Summary:Poly ADP‐ribose polymerase inhibitors (PARPi) have shown promising therapeutic efficacy in triple‐negative breast cancer (TNBC) patients. However, resistance ultimately develops, preventing a curative effect from being attained. Extensive investigations have indicated the diversity in the mechanisms underlying the PARPi sensitivity of breast cancer. In this study, we found that DNA damage binding protein 2 (DDB2), a DNA damage‐recognition factor, could protect TNBC cells from PARPi by regulating DNA double‐strand break repair through the homologous recombination pathway, whereas the depletion of DDB2 sensitizes TNBC cells to PARPi. Furthermore, we found that DDB2 was able to stabilize Rad51 by physical association and disrupting its ubiquitination pathway‐induced proteasomal degradation. These findings highlight an essential role of DDB2 in modulating homologous recombination pathway activity and suggest a promising therapeutic target for TNBC. We found that DNA damage binding protein 2 (DDB2), a DNA damage‐recognition factor, could protect triple‐negative breast cancer (TNBC) cells from poly ADP‐ribose polymerase inhibitors by regulating the homologous recombination pathway of DNA double‐strand break repair, whereas the depletion of DDB2 sensitizes TNBC cells to poly ADP‐ribose polymerase inhibitors. Furthermore, we found that DDB2 was able to stabilize Rad51 by disrupting its ubiquitination pathway‐induced proteasomal degradation. These findings highlight an essential role of DDB2 in modulating homologous recombination pathway activity and suggest a potential therapeutic target for TNBC.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.14201