Abstract 226: Transcriptional control of the BRCA1 expression by a metabolic switch

Abstract

Abstract Deletion or loss of BRCA1 function is the major cause of most familial forms of breast cancer, decreased expression of non-mutated BRCA1 alleles is often found in sporadic breast cancer, suggesting that alterations in BRCA1 transcriptional regulation may contribute to non-inherited forms of breast cancer. BRCA1 plays a central role in maintenance of genome stability and cell cycle control and therefore, often recognized as both a “care taker” and “gate keeper” of the genome. In this study, we show that BRCA1 expression is controlled by a tightly regulated dynamic balance between the association of transcriptional co-activators and co-repressors that regulate histone acetylation and chromatin accessibility at the BRCA1 promoter during the transcriptional response to estrogen stimulation. A central regulatory step in the control of the BRCA1 promoter is the eviction of the co-repressor and metabolic sensor C-terminal-binding protein1 (CtBP1). Loss of CtBP1 from the BRCA1 promoter either by estrogen induction, CtBP1 RNAi depletion or increasing NAD+/NADH ratio results in elevated histone acetylation, HDAC1 dismissal from the BRCA1 promoter and increased BRCA1 transcription. These findings indicate that BRCA1 expression is controlled by a metabolic switch that dynamically influences the localized deposition of epigenetic marks and chromatin structure at the BRCA1 promoter and suggests that caloric intake may influence the levels of this critical tumor suppressor in mammary tissues. Strikingly extended observation of other DNA damage response genes indicate that they are also under direct regulation by CtBP and CtBP complex. These data suggest a global molecular linkage between cellular metabolic status and the capacity to maintaining the genome free from damage or mistakes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 226. doi:10.1158/1538-7445.AM2011-226