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NUCLEAR RECEPTORS, ROS & CANCER BIOLOGY

ZHOU TING, BSc. (Hon) NGS Postgraduate Student Department of Physiology MD11, 10 Medical Drive, #B1-07 Email: g0701828@nus.edu.sg Major Supervisor: Prof. Shazib Pervaiz Co-supervisor: Dr. Alan Prem Kumar Tel: (65) 6516-4445 Fax: (65) 6773-5461

In addition to their role in lipid and glucose metabolism, peroxisome proliferator-activated receptor gamma (PPARy) play a role in cancer development and represent promising target for cancer prevention and treatment strategies. We showed inhibition of intracellular pH regulator, NHE1 expression by direct silencing or pre-incubation with H2O2 led to cells’ growth arrest and sensitization to death triggers. Therefore, downregulation of NHE1 gene expression could be a promising avenue in the search for new strategies to induce tumor cells’ growth arrest and increase sensitivity to anticancer treatment. Indeed, having identified a PPRE on NHE1 gene, we showed exposure of breast cancer cell lines to low concentrations PPARy ligands represses NHE1 gene expression. Inhibition of NHE1 sensitized these cell lines to paclitaxel. Remarkably, PPARy ligands at these concentrations do not downregulate NHE1 and do not affect viability of normal breast cells, because of their very low PPARy protein levels. Lately there is increasing evidence of cross talks between PPAR and ER pathways. Bearing in mind, the role of estrogen in the development of breast cancer, we identified a putative ERE in close proximity to PPRE on NHE1 gene. We, therefore, hypothesize that in ERα-positive breast cancer cells, there may exits a possible cross-talk between ERa and PPARy. This project proposes to first investigate if presence of serum estrogen reverses PPARy-mediated repression of NHE1 and to demonstrate the effect of estrogen is indeed ERa-dependent. Having established this, we would then assess the binding activity of ERα to NHE1 promoter. In light of increasing number of breast cancer patients acquiring resistance to currently used anti-estrogen therapies, our ultimate intention from this study is to understand the molecular mechanism by which ERα reverses PPARy-mediated repression of NHE1. We believe this project will shed new light in developing new approaches for combining therapeutic agents to possibly re-sensitize breast cancer patients who are resistant to anti-estrogen therapy alone.