Expression of the nuclear receptor peroxisome proliferator activated receptor delta (PPARδ) in breast cancer cells is negatively associated with patient survival, but the underlying mechanisms are not clear. High PPARδ protein levels in rat breast adenocarcinomas were found to be associated with increased growth in soft agar and mice. Transgenic expression of PPARδ increased the ability of human breast cancer cell lines to migrate in vitro and form lung metastases in mice. PPARδ also conferred the ability to grow in exhausted tissue culture media and survive in low-glucose and other endoplasmic reticulum stress conditions such as hypoxia. Upregulation of PPARδ by glucocorticoids or synthetic agonists also protected human breast cancer cells from low glucose. Survival in low glucose was related to increased antioxidant defenses mediated in part by catalase and also to late AKT phosphorylation, which is associated with the prolonged glucose-deprivation response. Synthetic antagonists reversed the survival benefits conferred by PPARδ in vitro. These findings suggest that PPARδ conditions breast cancer cells to survive in harsh microenvironmental conditions by reducing oxidative stress and enhancing survival signaling responses. Drugs that target PPARδ may have a role in the treatment of breast cancer.

Targeting the mechanisms that allow chronic lymphocytic leukemia (CLL) cells to survive in harsh cancer microenvironments should improve patient outcomes. The nuclear receptor peroxisome proliferator activated receptor delta (PPARδ) sustains other cancers, and in silico analysis showed higher PPARD expression in CLL cells than normal lymphocytes and other hematologic cancers. A direct association was found between PPARδ protein levels in CLL cells and clinical score. Transgenic expression of PPARδ increased the growth and survival of CD5 Daudi cells and primary CLL cells in stressful conditions including exhausted tissue culture media, low extracellular glucose, hypoxia and exposure to cytotoxic drugs. Glucocorticoids and synthetic PPARδ agonists up-regulated PPARD expression and also protected Daudi and primary CLL cells from metabolic stressors. Survival in low glucose was related to increased antioxidant expression, substrate utilization and mitochondrial performance, and was reversed by genetic deletion and synthetic PPARδ antagonists. These findings suggest PPARδ conditions CLL cells to survive in harsh microenvironmental conditions by reducing oxidative stress and increasing metabolic efficiency. Targeting PPARδ may be beneficial in the treatment of CLL.