PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions.
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.
Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
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Wang
Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
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Wang
Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
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Shi
Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
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Sun
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.|Transplant Research Division, Toronto General Hospital, Toronto, Ontario, Canada.
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Gorczynski
Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, China.
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Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
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Xu
Biology Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.|Department of Immunology, University of Toronto, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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