Activation of Peroxisome Proliferator-Activated Receptor-β/δ (PPAR-β/δ) Inhibits Human Breast Cancer Cell Line Tumorigenicity

The effect of activation and overexpression of the nuclear receptor PPAR-beta/delta in human MDA-MB-231 (estrogen receptor-negative; ER-) and MCF7 (estrogen-receptor-positive; ER dagger) breast cancer cell lines was examined. Target gene induction by ligand activation of PPAR-beta/delta was increased by overexpression of PPAR beta/delta compared with controls. Overexpression of PPAR-beta/delta caused a decrease in cell proliferation in MCF7 and MDA-MB-231 cells Compared with controls, whereas ligand activation of PPAR-beta/delta further inhibited proliferation of MCF7 but not MDA-MB-231 cells. Overexpression and/or ligand activation of PPAR-beta/delta in MDA-MB-231 or MCF7 cells had no effect on experimental apoptosis. Decreased clonogenicity was observed in both MDA-MB-231 and MCF7 overexpressing PPAR-beta/delta in response to ligand activation of PPAR-beta/delta as compared with controls. Ectopic xenografts developed from MDA-MB-231 and MCF7 cells overexpressing PPAR-beta/delta were significantly smaller, and ligand activation of PPAR-beta/delta caused an even greater reduction in tumor volume as compared with controls. Interestingly, the decrease in MDA-MB-231 tumor size after overexpressing PPAR-beta/delta and ligand activation of PPAR-beta/delta correlated with increased necrosis. These data show that ligand activation and/or overexpression of PPAR-beta/delta in two human breast cancer cell lines inhibits relative breast cancer tumorigenicity and provide further support for the development of ligands for PPAR-beta/delta to specifically inhibit breast carcinogenesis. These new cell-based models will be invaluable tools for delineating the role of PPAR-beta/delta in breast cancer and evaluating the effects of PPAR-beta/delta agonists. Mol Cancer Ther; 13(4); 1008-17. (C)2014 AACR.