Abstract B41: Molecular linkages between metabolic imbalance, genome stability, and triple-negative breast cancer

Abstract

Abstract Breast cancer remains a worldwide threat to public health with over one million new cases, and nearly half a million deaths each year. Defining the mechanisms underlying the causes and risks of breast cancer remains a major challenge to global health. Though numerous population-based studies have demonstrated a indisputable link between obesity and breast cancer, the underlying molecular mechanisms and their association with elevated circulating hormones and inflammatory cytokines remain poorly defined. Similarly, the reasons why young women of African descent show a nearly two fold higher frequency of the more aggressive forms of breast cancer including the Triple Negative and basal-like phenotypes, are not understood. Recently we have defined a role for the transcriptional repressor protein CtBP in the control of proteins important for DNA repair including the early onset breast cancer gene BRCA1. In response to elevated levels of the high energy metabolic intermediate, NADH (nicotinamide adenine dinucleotide), nuclear levels of CtBP are stabilized and target a transcriptional program that impairs DNA repair in breast cancer cells. Loss of CtBP or growth under calorie restricted conditions increases the ability of breast cancer cells to repair DNA damage. Genome-wide location analysis by chromatin immuno-precipitation combined with deep sequencing (ChIP-Seq) reveals that CtBP targets gene classes that play a significant role in epithelial-to-mesenchymal transition, genome stability and stem cell transcriptional programs. Moreover, by Kaplan-Meier survival analysis of several published gene expression studies, CtBP targeted gene lists distinguish breast cancer patients with worst outcome/survival. Finally, profiling of CtBP protein expression in tissue micro-array studies of breast cancer in African American and Nigerian populations demonstrates elevated levels of CtBP expression in patients with more aggressive disease phenotypes. We explore the role of CtBP and its gene regulatory network (the “CtBP Web”) in the population-based association of breast cancer with obesity and racial/ethnic groups at higher risk for triple negative breast cancer. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B41.