Abstract
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.
Highlights
A hallmark of lethal breast cancers is their ability to live in metabolic conditions that would otherwise kill normal cells.[1]
PPARδ levels were low or undetectable in four out of six of the non-aggressive clones that did not grow in soft agar
There are presently no clinically relevant PPARδ antagonists, but. The results in this manuscript indicate that PPARD is expressed by breast cancer cells with more aggressive clinical behavior (Figure 1)
Summary
A hallmark of lethal breast cancers is their ability to live in metabolic conditions that would otherwise kill normal cells.[1]. A better understanding of the mechanisms that allow breast cancer cells to survive in harsh conditions might identify new targets to improve therapeutic outcomes. The nuclear receptor peroxisome proliferator activated receptor delta (PPARδ) may be a central regulator of the ability of cells to thrive in harsh conditions. It is the least characterized of the nuclear receptor family that includes PPARγ and PPARα, which control fat storage in adipocytes and fatty acid oxidation in liver and muscle, respectively.[2] PPARδ is expressed ubiquitously and, in the absence of ligands, binds corepressors like NCOR1 and recruits histone deacetylases to repress gene expression. PPARδ is activated by high concentrations of free fatty acids, bioactive lipids and synthetic agonists such as GW501516 and GW0742.2
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