Abstract This study focuses on the key concept of “metabolic transduction” as an important general mediator of cellular reprogramming in epithelial cancers. As a result of multiple studies on epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition in diverse epithelial cancers, the role of developmental plasticity during epithelial differentiation has emerged as a new area of research. Recent data from our lab suggest that metabolites and intermediates in cellular metabolism can act as secondary messengers to dynamically change and globally reprogram epigenetic signatures during normal development, tissue repair, and cancer. We refer to this process as metabolic transduction. Central to this concept is the role played by the C-terminal binding proteins, CTBP1 and CTBP2. Dimeric combination of these factors act as metabolic sensors that function, in the presence of the high energy intermediate NADH, to target multiple classes of chromatin modifying factors, including histone deacetylase, histone methyl-transferases, histone demethylases, DNA methyl-transferases to specific locales throughout the genome. Therefore, CTBP has the potential to mediate widespread changes in the epigenetic landscape and influence broad programs of cellular behavior. Genome-wide profiling studies by ChIP-seq reveal that CTBP controls a network of genes linked to cellular events that influence cellular re-programing or “plasticity” including stem cell transcriptional programs, angiogenesis, and EMT. These studies combined with immuno-histochemical profiling of patient samples indicates that CTBP plays an important role in driving progression of more aggressive forms of breast cancer including Triple Negative Breast Cancer and the basal-like subtypes. Recent studies in our group suggest a role for CTBP in enabling plasticity of cellular fate in malignant cells. Breast cancer cell lines capable of spontaneous de-differentiation into side populations with tumor initiation cell characteristic, such as Sum149PT, are highly enriched in CTBP and are dominated by CTBP controlled pathways. This association has significance in diverse types of cancer, since other transformed cell lines capable of spontaneous de-differentiation into side population, including the endometrial carcinoma cell line HEC-1A, show similar enrichment and dependency on CTBP. These striking similarities suggest that CTBP may represent a driver of a tumor cell plasticity, implicating this tumor cell feature as a new hallmark of epithelial cancers. Therefore, strategies to target CTBP, and cellular reprogramming in general, may provide new opportunities for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5019. doi:1538-7445.AM2012-5019