Abstract The link between inflammation and cancer was proposed more than 150 years ago when Virchow suggested that malignancies tend to arise at sites of chronic inflammation. Recent studies have established that elevated levels of nitric oxide/reactive nitrogen species (NO/RNS) generated in the inflammatory microenvironment are associated with several conditions critical for initiation and promotion of cancer. The BRCA1 protein contributes to cell viability in multiple ways, including DNA repair, cell cycle checkpoint control, transcription, and regulation of chromosome segregation. Hundreds of mutations in the BRCA1 gene have been identified and associated with an increased risk of cancer. Sporadic breast carcinomas, on the other hand, rarely show mutations of this gene. Instead, BRCA1 protein expression is frequently reduced in sporadic cases. As sporadic tumors account for >90% of the breast cancer, considerable research is directed towards the identification of mechanisms that down-regulate the function of the wild type BRCA1 and lead to genetic instability. BRCA1 expression is negatively regulated at the transcriptional level by the repressive complex of retinoblastoma-like protein 2 (RBL2) and E2F4. Formation of the repression RBL2/E2F4 complex can be accelerated by, for example, RBL2 dephosphorylation. Recently, protein phosphatase 2A (PP2A), an enzyme responsible for RBL2 dephosphorylation, was shown to be nitrated and activated by NO/RNS (Ohama T., et al., JBC 285, 8711-18, 2010). In the present investigation I demonstrate that inflammatory levels of NO/RNS induce substantial dephosphorylation of RBL2. Normal human mammary epithelial cells (MCF-10A) were incubated with 0.1 mM of the NO-donor SNAP for 6 h. This concentration of NO-donor mimics the intracellular level of NO/RNS during chronic inflammation, hypoxia, and does not induce significant DNA damage and maintains the ATM/ATR-dependent pathways intact. After 6 h incubation with SNAP, significant decrease in total amount of BRCA1 protein was observed with no apparent changes in the levels of E2F1, E2F4, and the catalytic subunit of PP2A, all involved in the regulation of BRCA1. RBL2 dephosphorylation promotes a repressive RBL2/E2F4 complex formation, which inhibits expression of BRCA1. I hypothesize that NO/RNS generated by chronic inflammatory conditions posttranslationally modify proteins involved in the regulation of BRCA1 expression and downregulate BRCA1 expression, thereby constituting a critical role in genetic instability and ultimately carcinogenesis. 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 3926. doi:10.1158/1538-7445.AM2011-3926