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NUCLEAR RECEPTORS, ROS & CANCER BIOLOGY

LOO SER YUE BSc. Honors student Department of Physiology MD11, 10 Medical Drive, #B1-07 Email: u0503042@nus.edu.sg Major Supervisor: Prof. Shazib Pervaiz Co-supervisor: Dr. Alan Prem Kumar Tel: (65) 6516-4445 Fax: (65) 6773-5461

Peroxisome Proliferator-activated Receptor gamma (PPARg) is a transcription factor that exhibits anti-proliferative effects and induces differentiation in many cancer types. It is of particular interest in breast cancer due to the increased levels of PPARg in tumorigenic breast epithelial cells compared to normal breast cells, thus making it a suitable target as an anti-tumor agent. Recent reports show activation of PPARg increases mitochondrial reactive oxygen species (ROS) production, contributing to cytotoxic effects by mediating cell death. Our group has shown that cells’ response to death signaling is regulated by the ratio of intracellular superoxide to hydrogen peroxide, where a slight increase in intracellular superoxide level inhibits cell death while increased intracellular hydrogen peroxide sensitizes tumor cells to various death triggers. This project aims to find out if a mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD), is a target of PPARg. Promoter analysis shows a putative PPRE on human MnSOD promoter and studies in mouse models have also shown MnSOD to be a PPARg target. The first aim of this project is to observe the dose response of PPARg ligands, 15d-PGJ2 and glitazones, on MnSOD and Cu/Zn SOD expression levels in tumorigenic and normal human mammary cells. SOD activity will also be monitored. Tumorigenic cell lines to be used are MDA-MB-231 and MDA-MB-468 as they are invasive, ERa negative and express higher levels of MnSOD. Next, whether the changes in MnSOD levels are PPARg dependent will be determined by using GW9662, siPPARg and overexpressing PPARg. Intracellular ROS levels will also be monitored upon trigger and to determine if MnSOD is the source of ROS. Furthermore, the effect of PPARg ligands may be mediated by the direct binding of PPARg to its putative response element on the promoter region of MnSOD or by interfering with NF-kB activity, thus changing MnSOD expression. DNA binding assays will be used to explore this. We hypothesized that activated PPARg regulates MnSOD levels, which lead to changes in intracellular ROS levels – to mediate cell death. The relevance of MnSOD regulation can then be investigated by either over expressing MnSOD or knocking down its expression using MnSOD siRNA.