title: Cyclooxygenase-2 overexpression in the skin of transgenic mice results in suppression of tumor development.
abstract: Significant evidence has accumulated suggesting that the inducible form of cyclooxygenase (COX-2), a central enzyme in the prostaglandin biosynthetic pathway, plays an important role in tumor development. To better understand the role of COX-2 in tumorigenesis, we generated transgenic mice that overexpress COX-2 under control of the human keratin 14 promoter, which allows for expression in the epidermis and some other epithelia. Transgenic mice, referred to as K14.COX2 mice, were readily distinguished from their nontransgenic littermates by the appearance of significant alopecia. Administration of a specific COX-2 inhibitor restored hair growth, indicating that the alopecia was attributable to elevated COX-2 enzymatic activity. Unexpectedly, COX-2 overexpression was found to protect, rather than sensitize, K14.COX2 mice to skin tumor development induced by an initiation/promotion protocol. K14.COX2 transgenics developed tumors at a much lower frequency than did their littermate controls (3.3% versus 93%, respectively, on a FVB background and approximately 25% versus 100%, respectively, on an ICR background) and presented with significantly reduced tumor burdens (average, 0.03 versus 12.7 tumors/mouse, respectively, on a FVB background and 0.5 versus 7.1 tumors/mouse, respectively, on an ICR background). Mice fed a COX-2 inhibitor in utero and as weanlings up to the time of promotion also showed a significant resistance to tumor development. These results clearly raise questions regarding the role of COX-2 and elevated prostaglandin levels in skin tumor development.
authors: Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Oncology Drug Discovery, Princeton, New Jersey 08543, USA.
authors: David K
authors: DK
authors: Bol
authors: R Bruce
authors: RB
authors: Rowley
authors: Ching-Ping
authors: CP
authors: Ho
authors: Brigette
authors: B
authors: Pilz
authors: Janet
authors: J
authors: Dell
authors: Mavis
authors: M
authors: Swerdel
authors: Kaoru
authors: K
authors: Kiguchi
authors: Stephanie
authors: S
authors: Muga
authors: Russell
authors: R
authors: Klein
authors: Susan M
authors: SM
authors: Fischer
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000505:Alopecia / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D002273:Carcinogens; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D018859:Hair Follicle / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D011720:Pyrazoles; D012867:Skin / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate
chemical_list: D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D015127:9,10-Dimethyl-1,2-benzanthracene; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate