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

Abstract

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.

Bioinformatics Analysis Reveals Biomarkers With Cancer Stem Cell Characteristics in Lung Squamous Cell Carcinoma

“…High RAD51 expression enhances cancer progression through the p38/Akt/Snail signaling pathway (Chiu et al, 2019). RAD51 may lead to increased drug resistance in triple-negative breast cancer patients (Zhao et al, 2019) and is also associated with the radiosensitivity of some tumors, such as nasopharyngeal cancer (Zhang Z. et al, 2018) and prostate cancer (Maranto et al, 2018).…”

PARP inhibitors in metastatic prostate cancer: When, who, and how?

“…Increased RAD51 activity, either through downregulation of inhibitors such as EMI1/DDB2 or through upregulation of the TOPβ1 activator, allows HRR to bypass BRCA1 or 2 functions and leads to resistance. [99,100] Notably, bromodomain protein 4 overactivity leads to a similar rise in RAD51 activity which may be negated by using bromodomain inhibitors. [101,102] International Journal of Molecular and Immuno Oncology • Article in Press | 11…”

Biomarkers in Triple-Negative Breast Cancer: State-of-the-Art and Future Perspectives

“…The main mechanisms described are the reversion of BRCA and HRR gene mutations to wild-type, the demethylation of promoter of HR genes, the mitigation of replication stress, the mutations in PARP itself and/or drug efflux pumps [ 75 , 76 , 77 ]. In preclinical patient-derived BRCAm-xenograft (PDX) models, the detection of RAD51 foci, a surrogate biomarker of HRR functionality, correlated with resistance to PARPis regardless of the underlying mechanism restoring HRR function [ 78 , 79 , 80 , 81 , 82 ]. By using in vitro and in vivo models of intrinsic resistance to PARPis, Yu-Yi Chu et al described the role of proteins like RTK, c-MET in PARP inhibition resistance [ 83 , 84 ].…”