DDB2, a new regulator of metabolism and cell death in human breast tumor cells

The protein Damaged DNA Binding-2 (DDB2) is well known for its role in DNA repair by nucleotide excision repair. Interestingly, DDB2 is differentially expressed in breast cancer expressing the estrogen receptor alpha or not. Recent works performed in our laboratory showed a new role of DDB2 in the control of proliferation and invasive abilities in different breast tumor cells through its involvement in the transcriptional regulation of target genes. Two genes involved in tumorigenic processes, MnSOD (manganese superoxide dismutase) and IκBα (inhibitor alpha of Nuclear Factor-kappa B), have been found to be regulated by DDB2. In addition, transcriptomic analyses on cells that differentially express DDB2 showed that several genes involved in the regulation of cellular metabolism are modulated. Our aim is now to focus on the effects of DDB2 expression on cellular metabolism and glycolysis. The results indicated that the overexpression of DDB2 leads to a respiratory chain dysfunction and an increase of the glycolytic pathway. Moreover, we observed an increased production of reactive oxygen species in these cells, compared to parental cells. As mitochondria are involved in cell death, we performed different experiments to evaluate the impact of DDB2 in the response to anticancer agents (Doxorubicin, and 5-fluorouracile (5-FU)) commonly used in the treatment of breast cancer. Interestingly, the cells exhibit a greater sensitivity to anticancer drugs when DDB2 is overexpressed. As these two agents are related to DNA damaged, we have also used other molecules, the apoptotic inducer, TNFα (Tumor Necrosis Factor alpha), and the Paclitaxel (an antimicrotubule agent) to precise the role of DDB2 on cell death. Similar results were obtained, thus demonstrating the influence of DDB2 overexpression in the response to cell death. The identification of molecular mechanisms responsible for these cellular modifications could place DDB2 and these target genes as predictive markers of sensitivity to anticancer drugs in breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-01-04.