Suppression of Tumor Formation by a Cyclooxygenase-2 Inhibitor and a Peroxisome Proliferator-Activated Receptor γ Agonist in an In vivo Mouse Model of Spontaneous Breast Cancer

• Published in: Clinical cancer research 2008-08, Vol.14 (15), p.4935-4942
• Main Authors: MUSTAFA, Aladdin, KRUGER, Warren D
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - therapy; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; breast cancer; Celecoxib; Cell Line, Tumor; Cell Proliferation; COX-2; Cyclooxygenase 2 Inhibitors - pharmacology; Disease Progression; Female; Gynecology. Andrology. Obstetrics; Mammary gland diseases; Mammary Neoplasms, Animal - therapy; Medical sciences; Mice; Mice, Transgenic; Models, Biological; Pharmacology. Drug treatments; PPAR gamma - agonists; PPARγ; Pyrazoles - pharmacology; Sulfonamides - pharmacology; Time Factors; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0958

Purpose: Activation of COX-2 and inhibition of PPARγ have been observed in human and animal models of breast cancer. Both inhibition of COX-2 and activation of PPARγ can inhibit proliferation of breast cancer cells in vitro . Here, we examine the effects of the COX-2 inhibitor celecoxib and the PPARγ agonist N -(9-fluorenyl-methyloxycarbonyl)- l -leucine (F-L-Leu) on mouse breast tumor cells in vitro and in vivo . Experimental Design: We created and characterized a mouse mammary adenocarcinoma cell (MMAC-1) line from C3 (1)-SV40 tumor antigen mice to study COX-2 and PPARγ expression and response to celecoxib and F-L-Leu in vitro . To study the in vivo effects, C3 (1)-SV40 tumor antigen mice were given either control diet or diets containing three different concentrations of celecoxib and F-L-Leu as well as a combination of both agents. Mice were then followed for tumor formation up to 1 year. Results: MMAC-1 cells express both COX-2 and PPARγ mRNA and exhibited cooperative growth inhibition with a combination of celecoxib and F-L-Leu. In mice, the median age of death due to mammary tumors was significantly delayed in celecoxib-treated animals at all three concentrations but was not significantly affected by F-L-Leu treatment alone. A combination of celecoxib and F-L-Leu was significantly more effective than celecoxib alone. Conclusions: Our findings suggest that a combination of a COX-2 inhibitor and PPARγ agonist can delay breast cancer in a mouse model and suggest that these agents should be studied in the context of human populations with high breast cancer risk.