PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions

Expression of the nuclear receptor peroxisome proliferator activated receptor delta (PPARd) in breast cancer cells is negatively associated with patient survival, but the underlying mechanisms are not clear. High PPARd protein levels in rat breast adenocarcinomas were found to be associated with increased growth in soft agar and mice. Transgenic expression of PPARd increased the ability of human breast cancer cell lines to migrate in vitro and form lung metastases in mice. PPARd 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 PPARd 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 PPARd in vitro. These findings suggest that PPARd conditions breast cancer cells to survive in harsh microenvironmental conditions by reducing oxidative stress and enhancing survival signaling responses. Drugs that target PPARd may have a role in the treatment of breast cancer.