Magnitude of peroxisome proliferator-activated receptor-γ activation is associated with important and seemingly opposite biological responses in breast cancer cells

Background. The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) has become a potential target for the prevention and treatment of breast cancer. However, recent in vitro and in vivo studies have raised the question of whether activation of PPAR gamma leads to the promotion or reduction of tumor formation. Studies using several cancer cell lines, animal models, and a variety of PPAR gamma agonists have shown discordant results, including changes in cellular proliferation, differentiation, and apoptosis of cancer cells and tumors. Methods: We studied the effects of low-, moderate-, and high-dose treatment of the PPAR gamma ligands 15-deoxy-Delta (12,14)prostaglandin J(2) (15dPGJ(2)) and troglitazone (TGZ) on parameters of cell growth, differentiation, and apoptosis in the epithelial breast cancer cell line MDA-MB-231. Results: The biologic effects of these compounds depend largely on ligand concentration and the degree of PPAR gamma activation. For example, low concentrations of 15dPGJ(2) (<2.5 muM) and TGZ (<5 muM) increased cellular proliferation, but concentrations of 15dPGJ(2) greater than or equal to 10 muM and of TGZ at 100 muM blocked cell growth. TGZ (100 muM) slowed cell cycle progression, and 15dPGJ(2) (10 muM) caused an S-phase arrest in the cell cycle and induced morphological characteristics consistent with apoptosis. Expression of CD36, a marker of differentiation in these cells, was induced by 2.5 muM 15dPGJ(2) or 5 to 100 muM TGZ. However, higher concentrations of 15dPGJ(2) did not alter CD36 expression. Transcriptional activation studies demonstrated that 15dPGJ(2) is a more potent PPAR gamma ligand than TGZ. Regardless of the ligand used, though, low transcriptional activation correlated with an increased cellular proliferation, whereas higher levels of activation correlated with cell cycle arrest and apoptosis. Conclusions: PPAR gamma activation induces several important and seemingly opposite changes in neoplastic cells, depending on the magnitude of PPAR gamma activation. These data may explain, at least in part, some of the discordant results previously reported.