Abstract 5103: Crosstalk between osteoprotegerin (OPG), fatty acid synthase (FASN), and cyclooxygenase-2 (COX-2) in breast cancer: implications in carcinogenesis

Abstract

Abstract The cross-talk between malignant and nonmalignant cells in the tumor microenvironment, as maneuvered by cytokines/chemokines, drives breast cancer progression. We demonstrated that OPG is expressed and secreted at very high levels from the highly invasive breast cancer cell lines SUM149PT and SUM1315MO2 as compared to human normal mammary epithelial HMEC cells (1). OPG was involved in modulating aneuploidy, cell proliferation, and angiogenesis in breast cancer (1). Mass spectrometry analysis performed in this study revealed OPG interacts with fatty acid synthase (FASN), which is a key enzyme of the fatty acid biosynthetic pathway in breast cancer cells. Further, electron microscopy, immunofluorescence, and fluorescence quantitation assay highlighted the presence of a large number of lipid bodies (lipid droplets) in SUM149PT and SUM1315MO2 cells in comparison to HMEC. We recently showed upregulation of COX-2 inflammatory pathway and its metabolite PGE2 secretion in SUM149PT and SUM1315MO2 breast cancer cells (2). Interestingly, human breast cancer tissue samples displayed high expression of OPG, PGE2 and FASN. Immunofluorescence staining exposed the co-existence of COX-2 and FASN in the lipid bodies of breast cancer cells. We reasoned that there might be cross-talk between OPG, FASN, and COX-2 that sustains the inflammatory pathways in breast cancer. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 and FASN by recombinant human OPG (rhOPG). Treatment with FASN inhibitor C75 decreased the number of lipid body/cell, downregulated phosphorylation of ERK, GSK3β, and induced apoptosis by caspase-3 and caspapse-9 activation. Collectively, the novel biological cross-talk between OPG, FASN, and COX-2 advocates for combinatorial drug treatment to block these players of carcinogenesis as a promising therapeutic to target highly invasive breast cancer.