? Background. The breast cancer susceptibility gene-1 (BRCA1) encodes a tumor suppressor gene that is implicated in regulation of diverse cellular processes: 1) cell cycle progression; 2) DNA repair; 3) apoptosis; and 4) gene transcription. BRCA1 regulates various transcriptional pathways primarily via protein:protein interactions. However, its biological significance has not been well documented. Recently we found that BRCA1 regulates the expression of multiples genes involved in oxidative and xenobiotic stress using DNA microarray analysis' assay. ? ? Preliminary data and Hypothesis. Preliminary study shows that BRCA1 interacts with AhR and ARNT and enhances CYP1A1 gene expression regulated by the AhR agonists such as TCDD, lndole-3-carbino or 5F-203. Thus, we hypothesize that BRCA1 exerts its detoxification activity by physically associate with AhR and ARNT and regulates the expression of genes such as CYP1A1 in human breast cancer cells. ? ? Goals & Experimental Strategy. The major goals of this projects are; SA1. To determine physical association of BRCA1 with AhR and ARNT1. SA2. To determine effects of BRCA1 on AhR-mediated xenobiotic stress response. ? ? Significance. These studies suggest that a major mechanism by which BRCA1 downregulation or mutations lead to breast or ovarian cancer may be due to attenuated or defective function in detoxification of various drugs and foreign chemicals which utilize cytochrome 450 isoforms such as CYP1A1 and CYP1B1. These findings are relevant to the pathogenesis of hereditary and sporadic breast cancers. ? ?
| Kang, Hyo Jin; Kim, Hee Jeong; Kim, Sang Keun et al. (2006) BRCA1 modulates xenobiotic stress-inducible gene expression by interacting with ARNT in human breast cancer cells. J Biol Chem 281:14654-62 |
