Role of Cyclooxygenase-2 and Fatty Acid Synthase in Breast Cancer Development
Author | : Suying Lu |
Publisher | : |
Total Pages | : 348 |
Release | : 2008 |
ISBN-10 | : 0494398906 |
ISBN-13 | : 9780494398906 |
Rating | : 4/5 (06 Downloads) |
Download or read book Role of Cyclooxygenase-2 and Fatty Acid Synthase in Breast Cancer Development written by Suying Lu and published by . This book was released on 2008 with total page 348 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cyclooxygenase-2 (COX-2) and fatty acid synthase (FAS) are over-expressed in breast cancer. Inhibitors of COX-2 and FAS decrease proliferation and induce apoptosis in breast cancer cells. A previous study showed that the COX-2 inhibitor celecoxib not only inhibited rat mammary carcinogenesis, but also decreased fat deposition in rats fed a high fat diet, suggesting that celecoxib may affect lipid metabolism. We demonstrated that celecoxib suppresses FAS expression, and decreases fat accumulation by down-regulating c-Jun N-terminal kinase 1 (JNK1) in rats fed a high fat diet rich in n-6 polyunsaturated fatty acids (PUFAs). This finding suggests that not only inhibition of COX-2 but also down-regulation of FAS contribute to the chemopreventive effect of celecoxib. This observation led us to investigate the roles of both COX-2 and FAS in breast cancer development. We showed that COX-2 over-expression in breast epithelial cells inhibits proliferation, detachment-induced apoptosis and differentiation, and causes epithelial to mesenchymal transition (EMT). This finding suggests that COX-2 over-expression disturbs the homeostatic status of mammary epithelial cells, leading to partial transformation of these cells, and predisposing the mammary gland to tumorigenesis. Malignant transformation of breast epithelial cells is associated with elevated expression of FAS. We showed that inhibition of FAS by triclosan suppresses rat mammary tumorigenesis induced by N-methyl-N-nitrosourea (MNU). This finding suggests that FAS is a promising molecular target for breast cancer prevention. In cancers, de novo fatty acid synthesis is functionally linked to cell proliferation by providing fatty acids for the biosynthesis of cellular membranes, but the molecular link between these two processes was not known. We demonstrated that Sp1 coordinately regulates the expression of FAS, a key enzyme of fatty acid synthesis, and CDC25A, a key cell cycle protein, in estrogen-sensitive breast cancer cells. Thus, Sp1 is a molecular link between de novo lipogenesis and proliferation in these cells. Overall, findings of this thesis contribute to our knowledge relating to how COX-2 and FAS act to facilitate breast cancer development, and provide evidence that these enzymes could be potential targets for breast cancer prevention.