Abstract 819: Fatty acid synthase, cycloxygenase-2 (COX-2) and osteoprotegerin (OPG) expression in invasive breast cancer: Implications in carcinogenesis

Abstract

Abstract Breast cancer, the leading cause of death among women with an onset frequency of one in eight, is the most common type of cancer among women. However, despite the advancement in therapy, the mortality rate in breast cancer patients still remains high. The role of various different genes, directly or indirectly, regulating these processes have tremendously added to our knowledge of the complex process of proliferation, which has remained the most important prognostic factor so far. In our previous study, we established Osteoprotegerin (OPG)'s role in aneuploidy, cell proliferation and angiogenesis in breast cancer. 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 cells (HMEC). Here, we demonstrated by mass spectrometry that OPG pulls down fatty acid synthase (FASN), a key enzyme of the fatty acid biosynthetic pathway in breast cancer cells. We observed large number of lipid droplets in SUM149PT and SUM1315MO2 cells in comparison to HMEC by electron microscopy. Human breast cancer tissue samples showed high expression of FASN. Treatment with FASN inhibitor C75 decreased the number of lipid droplets/cell, altered expression of genes involved in cell proliferation, cell signaling (Akt/PI3K, ERK, GSK3β) apoptosis (caspase-3 and caspapse-9) and cell cycle. Treatment with C75 lowered the inflammatory pathway enzyme cyclooxygenase-2 (COX-2) expression and reduced secretion of its inflammatory metabolite prosataglandin E2 (PGE2). We reasoned that there might be crosstalk between OPG, FASN, and COX-2, that sustains the inflammatory pathways, and drives the progression of breast cancer. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 by recombinant human OPG. Collectively, our study indicates the crosstalk between FASN, COX-2 and OPG. Combinatorial drug treatment of these main players of carcinogenesis can be used as a potential therapeutic target to treat highly invasive breast cancer. Citation Format: Sudeshna Goswami, Neelam Sharma-Walia. Fatty acid synthase, cycloxygenase-2 (COX-2) and osteoprotegerin (OPG) expression in invasive breast cancer: Implications in carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 819. doi:10.1158/1538-7445.AM2015-819