Radiation response in cells derived from individuals with hereditary breast cancer / by Lindsay Sutherland.

Abstract

Inherited germline mutations in the tumour suppressor gene BRCA1 (BReast CAncer susceptibility gene 1) can lead to an increased risk for various cancers. Evidence now suggests that epigenetic changes resulting in reduced or absent expression of BRCA1 are also important causative factors. BRCA1 has many known roles, such as DNA damage repair, cell cycle control and regulation of transcription. In addition, a recent study has identified yet another function for BRCA1: to protect cells from oxidative stress, a contributory factor in the development of many cancers, including breast cancer. BRCA1 is known to stimulate Nrf2, a transcription factor that regulates the expression of phase II enzymes, which are important in the detoxification of chemical compounds. Sulforaphane (SFN), an antioxidant found in cruciferous vegetables such as broccoli, has also been found to stimulate expression of phase II enzymes. The purpose of this study was to investigate the cellular consequences of exposure to ionizing radiation in primary blood lymphocytes from healthy individuals compared to cells from individuals with mutations in BRCA1. These responses include DNA damage, increased levels of oxidative stress and decreased cell viability. A secondary aspect of this study was to investigate the protective effects of SFN on lymphocytes exposed to ionizing radiation. The results suggest that there was a greater decrease in cell viability in lymphocytes derived from individuals carrying a germline BRCA1 mutation upon radiation exposure. It was also found that SFN did not protect cells against the damaging effects of ionizing radiation. This loss of viability correlated with an increase in DNA damage. However, these results are obtained from a limited sample size. The major accomplishments of this study were the development of techniques to study radiation responses using lymphocytes. To more completely investigate the questions of whether a germline mutation in BRCA1 significantly impacts the cellular radiation response, and whether the dietary antioxidant SFN protects cells from the damaging impact of radiation, a larger sample size is needed in order for the results to be statistically significant.