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Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer

Lee, Kevin J ; Piett, Cortt G ; Andrews, Joel F ; Mann, Elise ; Nagel, Zachary D ; Gassman, Natalie R Cohen-Armon, Malka

PloS one, 2019-10, Vol.14 (10), p.e0223725-e0223725 [Periódico revisado por pares]

United States: Public Library of Science

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Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer
Autor: Lee, Kevin J ; Piett, Cortt G ; Andrews, Joel F ; Mann, Elise ; Nagel, Zachary D ; Gassman, Natalie R
Cohen-Armon, Malka
Assuntos: Adenosine diphosphate ; AP endonuclease ; Base excision repair ; Biology and life sciences ; Biotechnology ; Breast cancer ; Cancer genetics ; Cancer therapies ; Care and treatment ; Cell Line ; Cell Line, Tumor ; Damage assessment ; Damage localization ; Defects ; Deoxyribonucleic acid ; DNA ; DNA Damage ; DNA polymerase ; DNA Repair ; DNA-directed DNA polymerase ; EDTA ; Endonuclease ; Fibroblasts ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes ; Genetic aspects ; Genomes ; Hormones ; Humans ; Hydrolases ; Hypersensitivity ; Ligases ; Localization ; Medical schools ; Medicine ; Medicine and Health Sciences ; Menopause ; Mitochondrial DNA ; Monosaccharides ; Mutation ; Nucleases ; Nuclei (cytology) ; Overexpression ; Poly(ADP-ribose) ; Poly(ADP-ribose) polymerase ; Poly(ADP-ribose) Polymerase 1 ; Polymerase chain reaction ; Position (location) ; Protein Transport ; Proteins ; Public health ; Repair ; Research and Analysis Methods ; Ribose ; Target recognition ; Therapeutic applications ; Triple negative breast cancer ; Triple Negative Breast Neoplasms - genetics ; Tumors ; X-ray Repair Cross Complementing Protein 1 - genetics ; X-ray Repair Cross Complementing Protein 1 - metabolism ; XRCC1 protein
É parte de: PloS one, 2019-10, Vol.14 (10), p.e0223725-e0223725
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Competing Interests: The authors have declared that no competing interests exist.
Descrição: DNA repair defects have been increasingly focused on as therapeutic targets. In hormone-positive breast cancer, XRCC1-deficient tumors have been identified and proposed as targets for combination therapies that damage DNA and inhibit DNA repair pathways. XRCC1 is a scaffold protein that functions in base excision repair (BER) by mediating essential interactions between DNA glycosylases, AP endonuclease, poly(ADP-ribose) polymerase 1, DNA polymerase β (POL β), and DNA ligases. Loss of XRCC1 confers BER defects and hypersensitivity to DNA damaging agents. BER defects have not been evaluated in triple negative breast cancers (TNBC), for which new therapeutic targets and therapies are needed. To evaluate the potential of XRCC1 as an indicator of BER defects in TNBC, we examined XRCC1 expression in the TCGA database and its expression and localization in TNBC cell lines. The TCGA database revealed high XRCC1 expression in TNBC tumors and TNBC cell lines show variable, but mostly high expression of XRCC1. XRCC1 localized outside of the nucleus in some TNBC cell lines, altering their ability to repair base lesions and single-strand breaks. Subcellular localization of POL β also varied and did not correlate with XRCC1 localization. Basal levels of DNA damage correlated with observed changes in XRCC1 expression, localization, and measure repair capacity. The results confirmed that XRCC1 expression changes indicate DNA repair capacity changes but emphasize that basal DNA damage levels along with protein localization are better indicators of DNA repair defects. Given the observed over-expression of XRCC1 in TNBC preclinical models and tumors, XRCC1 expression levels should be assessed when evaluating treatment responses of TNBC preclinical model cells.
Editor: United States: Public Library of Science
Idioma: Inglês

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Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer

Lee, Kevin J ; Piett, Cortt G ; Andrews, Joel F ; Mann, Elise ; Nagel, Zachary D ; Gassman, Natalie R Cohen-Armon, Malka

United States: Public Library of Science

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