Physiological Functions and Metabolism of COX

Prostaglandin metabolism plays a pivotal role in inflammatory processes and has also been demonstrated to have a role in carcinogenesis, tumor differentiation and tumor growth in breast cancer. Cyclooxygenase-2 (COX-2) is the key involved enzyme, as it triggers prostaglandin synthesis. We reviewed the current literature regarding the impact of prostaglandin metabolism on breast cancer and illustrated the current evidence of the COX-2 influence on breast cancer, delineating possible future prophylactic and therapeutic strategies. Comprising 28.9 % of all carcinomas and 17.6 % of total cancer deaths of women in Europe, breast cancer is the most significant malignancy in females (1). The molecular characterization of the malignancy is an indicator for tumor prognosis and aggressiveness and may contribute to routine clinical decision making. Additionally, identifying specific molecular patterns helps to introduce individually targeted therapies for cancer treatment (2, 3). Classical molecular prognostic parameters of breast cancer are estrogen and progesterone receptor expression and HER-2 receptor expression (2, 3). Furthermore, increased levels of urokinasetype plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) correlate with a poor outcome in breast cancer (4). Recent studies have defined new biomarkers correlated to a poor prognosis: prostaglandin E2 (PGE2) and associated proteins in the cyclooxygenase (COX)-system (5-15). As a result, the activity of the COX system in breast cancer is under intense evaluation. In human breast cancer, the concept of inflammation as a critical component of tumor progression has been thoroughly investigated regarding the molecular processes. It is now becoming clear that the tumor microenvironment, which is characterized by inflammatory cells, participates in the neoplastic process by fostering proliferation, survival and migration of tumor cells conducted by receptors for invasion, migration and metastasis (16). COX-2 plays a crucial role as a prognostic factor for malignancy (17) and has been associated with carcinogenesis, particularly neoangiogenesis and tumor progression (5, 9, 11-12, 14-15). Physiological Functions and Metabolism of COX Prostaglandins are synthesised from free arachidonic acid by two isoenzymes: cyclooxygenase (COX) 1 and 2. COX-1 and -2 trigger the catabolism of arachidonic acid to prostaglandin G2 (PGG2). PGG2 is converted to prostaglandin H2 (PGH2) by a glutathione-dependent peroxidase. PGH2 constitutes the basic metabolite for different subtypes of prostaglandins which are involved in inflammatory processes (18). These different subtypes of prostaglandins are synthezised by microsomal or cytosolic prostaglandin synthases which are specific in different cells and tissues. Prostaglandin E synthase (PGES) triggers the conversion of PGH2 to PGE2 (Figure 1). Prostaglandins are synthezised in a variety of different tissues and act as autocrine and paracrine factors. Different subtypes of prostaglandins are generated according to the specific subtypes of enzymes in a specific cell (19). Prostaglandins exert their function by ligand binding to specific prostaglandin receptors. These receptors are Gprotein receptors; for example, signal transduction induced angiogenesis. Prostaglandins are catabolized by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Thus, as the key enzymes of arachidonic acid metabolization, COX-1 and -2 play pivotal roles in inflammatory processes. COX-1 is expressed ubiquitously but it does not constitute a significant 4359 Correspondence to: Marc Thill, MD, Ph.D., Department of Gynecology and Obstetrics, University Hospital of SchleswigHolstein, Luebeck Campus, Ratzeburger Allee 160, 23538 Luebeck, Germany. Tel: +49 4515002134, Fax: +49 4515002139, e-mail: [email protected]