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NUCLEAR RECEPTORS, ROS & CANCER BIOLOGY

CHEN LUXI, BSc. (Hon) Postgraduate Student National University Medical Institutes MD11, 10 Medical Drive, #B1-07 Email: g0800066@nus.edu.sg Major Supervisor: Dr. Alan Prem Kumar Co-supervisor: Dr. Lina Lim Tel: (65) 6516-4445 Fax: (65) 6773-5461

Annexin-A1 (ANXA1), a calcium-dependent phospholipids-binding protein, has been implicated to have correlation with the development of breast tumorigenesis. However, current data on the exact role of ANXA1 in breast cancer were limited and have been conflicting. Preliminary data demonstrated that ANXA1 expression could be up-regulated in MCF-7 human breast tumor cells when exposed to high pharmacological levels of estrogen for prolonged period of time, suggesting that the contradictory data on the expression of ANXA1 in breast cancer could be correlated to the estrogen receptor status. Peroxisome proliferator-activated receptor-y (PPAR-y), a nuclear hormone ligand-activated receptor, has been suggested to exhibit anti-tumor activity. PPAR-y expression is not restricted to adipose tissue. An increase in PPAR-y expression has been reported in several epithelial cancer cells. In addition, previous studies have suggested a possible role for ligand-activated PPAR-y, as an anti-tumor agent in differentiation-based therapy of breast cancer. PPAR-y has been identified to act as a transcription factor, we hence hypothesize that ANXA1 could be one of the target gene of PPAR-y, and the expression of ANXA1 in breast cancer cells may be dependent on the activation of PPAR-y by its agonists. Using MCF-7 human breast tumor cells as the model system for breast cancer, we demonstrated that ligand-activated PPAR-y up-regulates ANXA1 mRNA expression in a dose-dependent and PPAR-y-dependent manner. Interestingly, ANXA1 and PPAR-y expressions levels are inversely correlated when comparing breast cancer cell lines (MCF-7 and MDA-MB-231) against a normal breast epithelial cell line (MCF10A). Further, over-expression of ANXA1 in MCF-7 cells led to a better cell survival upon 15d-PGJ2 treatments, whereas knocking down ANXA1 increased sensitivity of cells to 15d-PGJ2 treatment. In this study, the first objective is to investigate the effects of PPAR-y ligands on ANXA1 expression in breast cancer cells. Secondly, we will move on to study the effect of changes in ANXA1 levels in viability and proliferation of breast cancer cells. From this study, we hope to elucidate the physiological mechanisms by which PPAR-y elicits its anti-tumor activity via regulation of ANXA1 expressions. Our findings may shed new insight into possible pharmacological strategies for breast cancer treatment.