Enhanced DNA damage response through RAD50 in triple negative breast cancer resistant and cancer stem‐like cells contributes to chemoresistance. (3rd November 2020)

• Record Type: Journal Article
• Authors: Abad, Etna; Civit, Laia; Potesil, David; Zdrahal, Zbynek; Lyakhovich, Alex
• Is Part Of: FEBS journal. Volume 288:Number 7(2021)
• Page Start: 2184
• Page End: 2202
• Publication Date: 2020-11-03
• Subjects: cancer stem cells -- chemoresistance -- DNA damage repair -- RAD50 -- triple‐negative breast cancer; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.15588
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : A growing body of evidence supports the notion that cancer resistance is driven by a small subset of cancer stem cells (CSC), responsible for tumor initiation, growth, and metastasis. Both CSC and chemoresistant cancer cells may share common qualities to activate a series of self‐defense mechanisms against chemotherapeutic drugs. Here, we aimed to identify proteins in chemoresistant triple‐negative breast cancer (TNBC) cells and corresponding CSC‐like spheroid cells that may contribute to their resistance. We have identified several candidate proteins representing the subfamilies of DNA damage response (DDR) system, the ATP‐binding cassette, and the 26S proteasome degradation machinery. We have also demonstrated that both cell types exhibit enhanced DDR when compared to corresponding parental counterparts, and identified RAD50 as one of the major contributors in the resistance phenotype. Finally, we have provided evidence that depleting or blocking RAD50 within the Mre11–Rad50–NBS1 (MRN) complex resensitizes CSC and chemoresistant TNBC cells to chemotherapeutic drugs. Abstract : Chemoresistant cancer cells are a recurring issue for tumour treatment and there is urgent need to identify the molecular pathways leading to chemoresistance. Data suggest that chemoresistant and cancer stem cells (CSCs) share commonalities and are a prime target to overcome resistance. Now, Alex Lyakhovich and colleagues identify enriched proteins using comparative proteomics on CSCs and chemoresistant cells from triple‐negative breast cancer cells. Among others, they find abundance for factors from the DNA damage response and show that depletion of the DSB repair protein RAD50 resensitizes cells to chemotherapeutic drugs, which points to RAD50 as a potential therapeutic target.