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In vitro Effects of Selenium on DNA Damage in BRCA1 Cell Lines

Abstract
Cancer of the breast is the most common cancer affecting women, with a 1 in 9 lifetime risk of developing breast cancer. Carriers of mutations in the breast cancer susceptibility gene, BRCA1, present with an increased lifetime risk of 80-95% of developing breast cancer. BRCA1 is a tumour-suppressor gene that is involved in DNA repair of double-strand breaks and transcriptional regulation. Studies have shown that oral supplementation with Selenium (Se) could potentially be an effective preventive agent against BRCA1-mutation carriers. Se is an essential trace mineral that plays critical roles in maintaining health in humans. Se functions by protecting lipid membranes, proteins and DNA from free radical damage and is involved in redox regulation in the cell. These functions are mediated through specific Se-dependent proteins termed selenoproteins, in which Se is incorporated. Se supplementation may exert its benefits by enhancing the DNA damage repair response. The effects also appear to be dependent on selenoprotein genotypes and concentration of Se in the body/diet. It is possible that Se supplementation may be effective in reducing the risk of breast cancer in BRCA1 carriers, but the use of organic Se compounds is likely to be preferable, but the dose-response needs to be determined. The objectives of this research thesis are to evaluate the dose-response of sodium selenite and methylseleninic acid (MSA) in two BRCA1-mutated cancer cell lines in vitro. The MTT assay was used to monitor cell activity, along with the comet assay to evaluate the DNA damage level using a dose-response curve of the two Se compounds on control and bleomycin-induced DNA damaged cells. In addition, DNA from each cell line was sequenced to confirm the presence of the published BRCA1 mutation. The data presented within this thesis demonstrates that a commonly-used inorganic form of Se, sodium selenite, is more genotoxic than the organic Se compound, MSA, in malignant BRCA1-mutated cells. Sodium selenite also has more direct cytotoxicity in BRCA1-mutated cells than MSA, as demonstrated by the MTT assay. However the enhanced repair capacity from Se on DNA damage in cells demonstrated by others has not been reproduced. Preliminary data showed potential at much lower doses (2 μM) of Se. Interestingly, the volatile metabolites produced from MSA appear to reduce DNA damage, supportive of this hypothesis. In order to understand if the effects observed are linked specifically to the BRCA1 mutation or breast cancer in general, future research should include the investigation of the effects of Se on breast cancer using alternative breast cancer cell lines, as well as non-malignant cells.
Type
Thesis
Type of thesis
Series
Citation
Mayall, K. R. (2015). In vitro Effects of Selenium on DNA Damage in BRCA1 Cell Lines (Thesis, Master of Science (Research) (MSc(Research))). University of Waikato, Hamilton, New Zealand. Retrieved from http://hdl.handle.net/10289/11481
Date
2015
Publisher
University of Waikato
Rights
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