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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Albarakati, Nada (2015)
Languages: English
Types: Unknown
Subjects:

Classified by OpenAIRE into

mesheuropmc: skin and connective tissue diseases
BRCA1 germ-line mutations predispose to hereditary breast and ovarian cancers. Cells lacking functional BRCA1 protein are deficient in the homologous recombination DNA repair pathway. Base excision repair (BER) is essential for processing base damage induced by endogenous and exogenous sources. Recently, BRCA1 was shown to transcriptionally regulate expression of genes involved in BER. The primary aim of the work described in this thesis was to investigate whether targeting the double-strand break pathway in BRCA1-BER deficient cells using ATM or DNA-PKcs inhibitors would be synthetically lethal. \ud \ud \ud DNA repair gene and protein expression in BRCA1 deficient and proficient cells were investigated. Initially 84 DNA repair genes were investigated. Data demonstrated down-regulation of several DNA repair mRNAs in BRCA1 mutant/knockdown cell lines as compared to proficient cell lines. RT-qPCR was performed for selected DNA repair genes and confirmed statistically significant down-regulation of these genes. Protein expression of the selected group was assessed and showed down-regulation. These results suggest that BRCA1 deficiency may be associated with a global defect in the BER pathway.\ud \ud BRCA1 deficient cells were targeted by ATM/DNA-PKcs inhibitors. BRCA1-BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. This in vitro study suggests that a potential synthetic lethality relationship exists between BRCA1 deficiency and ATM/DNA-PKcs inhibition. Moreover, results support the hypothesis that cisplatin increases the efficacy of ATM and DNA-PKcs inhibition in BRCA1 deficient cells. Taken together, this study provides the pre-clinical evidence that ATM and DNA-PKcs could be alternative synthetic lethality targets in BRCA1 deficient breast cancer.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 2.3.9.1. Background principles ....................................................... 79 2.3.9.2. Preparation of cell lysate .................................................... 79 2.3.9.3. Protein quantification (Bradford assay) .................................... 80 2.3.9.4. Preparation of cell lysates for electrophoresis .............................. 80 2.3.9.5. Polyacrylamide gel electrophoresis and Protein transfer .................. 80 2.3.9.6. Immunoblotting .............................................................. 81 2.3.9.7. Primary antibodies ........................................................... 82 2.3.9.8. Data analysis ................................................................. 82 3.
    • DNA repair profiling in BRCA1 deficient and proficient cells ................................ 84 Introduction .................................................................. 84 BRCA1 mutation in breast cancer cell lines................................ 85 Rationale for the study....................................................... 86 3.3.5. DNA repair protein expression is down-regulated in BRCA1 deficient cell lines compared to BRCA1 proficient cell lines. ......................................... 106 3.3.7. Quantification of DNA repair mRNA and protein expression in BRCA1 deficient and BRCA1 proficient cells. ........................................................ 110 3.4.2. Loss of BRCA1 expression is associated with reduction in expression of Homologous recombination factors ................................................ 120 3.4.3. Loss of BRCA1 expression is associated with reduction in expression of Nonhomologous end joining factors .................................................... 122 10
    • Conclusions ................................................................ 200 7.
    • General Discussion and suggestions for future studies .......................................... 203 7.1.
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