COX-2 and PPARgamma: Targets for BRCA Prevention

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DESCRIPTION (provided by applicant): Cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor-gamma (PPARgamma) have emerged as promising candidates for the prevention of breast cancer. Our studies and those of others suggest that COX-2 induction and inactivation of PPARgamma occur in breast cancer and that they contribute to cancer induction either directly or via their coordinate action on an array of proliferation- and apoptosis-related genes. Preliminary studies indicate that targeting both COX-2 and PPARgamma can inhibit mammary cancer to an extent superior to that produced by targeting each molecule alone. We hypothesize that simultaneous targeting of COX-2 and PPARgamma may act synergistically to inhibit the development of mammary gland carcinogenesis, which would be more effective than targeting each molecule alone. Furthermore, COX-2 inhibitors and/or PPARgamma-agonists induce common pro-apoptotic signaling pathways as a mechanism that mediates their cancer chemopreventive action. To test our hypothesis, we will assess the efficacy of a novel combinational regimen of the PPARgamma-ligand N-(9- fluorenyl-methyloxycarbonyl)-L-Leucine (F-L-Leu) and the COX-2 inhibitor celecoxib on the prevention of N-methyI- N-nitrosourea (MNU)-induced mammary cancer in female Sprague Dawley rats, a well-established animal model of breast cancer. To elucidate the mechanisms by which COX-2 inhibitors and PPARgamma-ligands prevent mammary cancer, the effects of celecoxib and F-L-Leu (separately and in combination) will be examined (both in normal tissues and at different cancer stages) on genes/proteins that play a critical role in mediating intrinsic apoptotic signaling in the mammary gland. We plan to accomplish the following specific aims: Aim 1: determine the dose-response effects of F-L-Leu and celecoxib, separately, on the prevention of rat mammary cancer. Aim 2: determine the synergistic preventive efficacy of a combination of the test drugs on rat mammary cancer. Aim 3: elucidate the mechanisms by which the test drugs prevent mammary gland carcinogenesis by evaluating their effects on molecular pathways that initiate apoptotic signaling in the mammary gland. This is the first detailed preclinical effort to evaluate targeting COX-2 and PPARgamma simultaneously as a novel strategy for breast cancer prevention. The results of this study can: i) provide insight into the synergistic interaction between COX-2 inhibitors and PPARgamma-ligands, ii) elucidate the mechanisms by which these agents mediate cancer prevention and iii) establish the basis for their eventual clinical use in the prevention of human breast cancer.