The Impact of BRCA2 on Homologous Recombination and PARP Inhibitor Sensitivity Examined in BRCA2 Heterozygous Cell Lines

• Main Author: Stefán Þór Hermanowicz 1989-
• Other Authors: Háskóli Íslands
• Format: Thesis
• Language: English
• Published: 2015
• Subjects: Líf- og læknavísindi; Brjóstakrabbamein; Erfðafræði; Frumulíffræði; Iceland
• Online Access: http://hdl.handle.net/1946/21851

The genome is under constant assault from exogenous and endogenous forces that can cause aberrations within the DNA. Cells depend on competent DNA repair systems to deal with these aberrations, one of these being homologous recombination. BRCA2, a protein long implicated in breast cancer, plays a key role in carrying out successful homologous recombination. PARP-1, another protein involved in DNA repair, has recently become the target of cancer therapy by exploiting the synthetic lethality observed when PARP1 is inhibited in the absence of BRCA2. This treatment has shown to be effective in treating tumors that are completely deficient in BRCA2 and having little impact on normal tissue containing two functional copies of BRCA2. However, little is known about the effect of PARP inhibitors on heterozygous tumors and normal tissue of BRCA2 mutation carrier. In Iceland, a founder mutation in BRCA2 called 999del5 is found within the population and is present in a significant amount of breast cancer patients. This study looked at the impact being a carrier for the 999del5 mutation has on the ability to respond to a PARP inhibitor and the capability for successful homologous recombination. This was done through the use of a BRCA2 heterozygous epithelial breast cell line. The results show that cells heterozygous for BRCA2 are tolerant to PARP inhibition and display competent yet diminished ability for homologous recombination. In conclusion, cells from individuals heterozygous for 999del5 are likely to be tolerant to PARP inhibition, despite slightly impaired HR. However, a minor impairments in HR over a lifetime might result in the accumulation of mutation, possibly explaining the increased risk of tumor formation in these individuals.