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

Abstract

Activation of COX-2 and inhibition of PPARgamma have been observed in human and animal models of breast cancer. Both inhibition of COX-2 and activation of PPARgamma can inhibit proliferation of breast cancer cells in vitro. Here, we examine the effects of the COX-2 inhibitor celecoxib and the PPARgamma agonist N-(9-fluorenyl-methyloxycarbonyl)-l-leucine (F-L-Leu) on mouse breast tumor cells in vitro and in vivo. We created and characterized a mouse mammary adenocarcinoma cell (MMAC-1) line from C3 (1)-SV40 tumor antigen mice to study COX-2 and PPARgamma 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. MMAC-1 cells express both COX-2 and PPARgamma 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. Our findings suggest that a combination of a COX-2 inhibitor and PPARgamma 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.