Activation of peroxisome proliferator-activated receptor-ß/δ (PPAR-ß/δ) inhibits human breast cancer cell line tumorigenicity.

ABSTRACT

The effect of activation and overexpression of the nuclear receptor PPAR-ß/δ in human MDA-MB-231 (estrogen receptor-negative; ER(-)) and MCF7 (estrogen-receptor-positive; ER(+)) breast cancer cell lines was examined. Target gene induction by ligand activation of PPAR-ß/δ was increased by overexpression of PPAR-ß/δ compared with controls. Overexpression of PPAR-ß/δ caused a decrease in cell proliferation in MCF7 and MDA-MB-231 cells compared with controls, whereas ligand activation of PPAR-ß/δ further inhibited proliferation of MCF7 but not MDA-MB-231 cells. Overexpression and/or ligand activation of PPAR-ß/δ 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-ß/δ in response to ligand activation of PPAR-ß/δ as compared with controls. Ectopic xenografts developed from MDA-MB-231 and MCF7 cells overexpressing PPAR-ß/δ were significantly smaller, and ligand activation of PPAR-ß/δ caused an even greater reduction in tumor volume as compared with controls. Interestingly, the decrease in MDA-MB-231 tumor size after overexpressing PPAR-ß/δ and ligand activation of PPAR-ß/δ correlated with increased necrosis. These data show that ligand activation and/or overexpression of PPAR-ß/δ in two human breast cancer cell lines inhibits relative breast cancer tumorigenicity and provide further support for the development of ligands for PPAR-ß/δ to specifically inhibit breast carcinogenesis. These new cell-based models will be invaluable tools for delineating the role of PPAR-ß/δ in breast cancer and evaluating the effects of PPAR-ß/δ agonists.