Breast cancer is the most common malignancy affecting women in developed countries. The BRCA1 and BRCA2 germline mutations predispose carriers to breast and ovarian cancers and account for approximately 10% of all breast cancer cases. Diets rich in micronutrients, such as carotenoids, folate, vitamin C and E are associated with reduced breast cancer risk. / Folate functions in one-carbon metabolism, and is an important factor in DNA-synthesis, DNA repair as well as DNA methylation. Moderate folate deficiency induces global DNA hypomethylation, gene promoter CpG hypermethylation and excessive uracil incorporation into DNA, causing genome instability and successively increasing cancer risk. Genome instabilities such as chromosome 17 mal-segregation and Her2 amplification are frequently observed in human breast tumours. / Methionine, another key factor in one-carbon metabolism, is the sole methy-donor for DNA methylation. Many human tumours are methionine-dependent, a phenotype characterised by the inability of cells to grow when methionine is replaced by its precursor homocysteine, causing elevated homocysteine levels, global DNA hypomethylation when methionine is restricted. In addition, genetic polymorphisms may affect enzyme activity and modulate cancer risk. / This thesis describes a study on the impact of selected nutrients, growth hormones and in vivo genome stability on breast cancer risk in BRCA1 or BRCA2 germline mutation carriers. Peripheral blood lymphocyes of BRCA germline mutation carriers and healthy non-carrier controls were studied for the impact of folic acid deficiency on genome damage and the methionine-dependence phenotype (MDP; in combination with common polymorphisms in one-carbon metabolism) on breast cancer risk, respectively. Plasma IGF-1 and IGFBP-3 were determined and chromosome 17 aneuploidy and Her2 amplification were assessed in mononucleated lymphocytes to establish the association of these markers on breast cancer risk in BRCA germline mutation carriers, independently or in combination with plasma folate, vitamin B12, homocysteine, selenium and common gene variants in the one-carbon metabolism, DNA repair genes or glutathionine S-transferase. / Results indicated that folic acid deficiency was a much more important factor affecting chromosome instability than carrying a BRCA1 or a BRCA2 germline mutation. In addition, MDP was associated with development of breast cancer in BRCA1 germline mutation carriers and appeared to be affected by common polymorphisms in methyltetrahydrofolate reductase. The methionine synthase (MTR) A2756G polymorphisms was associated with elevated cell growth when methionine is present in excess and was the only polymorphism studied that was associated with breast cancer risk in BRCA1 and BRCA2 germline mutation carriers. In addition, chromosome 17 aneuploidy, Her2 amplification and plasma IGF-1 and IGFBP-3 did not directly affect breast cancer risk; however, these biomarkers were significantly correlated with each other and MTR A2756G, suggesting a common mechanism for their inter-relationship. Plasma folate, vitamin B12, homocysteine and selenium of BRCA1 and BRCA2 germline mutation carriers were not associated with breast cancer risk and did not differ from non-carrier relatives. Further research with larger study populations are required to confirm these findings. / Thesis (PhDPharmacy)--University of South Australia, 2006.
| Identifer | oai:union.ndltd.org:ADTP/267269 |
| Creators | Beetstra, Alexandra Johanna Nicolaas. |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | copyright under review |
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