The peroxisome proliferator activated receptors (PPARs) alpha and gamma control breast cancer growth by activating p16^INK4A gene expression Free

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Peroxisome proliferator-activated receptors (PPARs) α and γ are nuclear receptors activated by endogenous fatty acids and derivatives, as well as the synthetic drugs fibrates and thiazolidinediones (TZDs), respectively. To date, fibrates are currently used for their hypolipidemic action in the prevention of cardiovascular diseases, and TZDs are administrated to type II diabetic patients for the treatment of insulin resistance. More recently, TZDs have also been reported to affect cell proliferation/differentiation pathways in various malignancies, including breast cancer. However, the molecular targets of PPARγ mediating these effects are not well known. Here, we demonstrate using the T-47D human breast cancer cell line as in vitro model that both PPARs inhibit mammary cancer cell-cycle progression at the G₁/S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16^INK4A (p16). The stimulatory effect of each PPAR on p16 gene transcription involves its binding to a canonical “PPAR-response element” and its interaction with the transcription factor Sp1 at a specific proximal Sp1-binding element in the p16 promoter. Correlating with this, a statistic profiling of 94 unselected primary human breast tumour samples demonstrated that p16 mRNA levels correlate to levels of both PPARs. Strikingly, PPARα, but not PPARγ, gene expression was furthermore associated to a longer relapse-free and overall survival in univariate analyses. Taken together these results identify an unexpected role for PPARα in breast cancer control and demonstrate that both PPARs inhibit breast cancer proliferation through p16. Thus, the PPAR/p16 pathway may be a potential novel pharmacological target for the prevention and/or treatment of breast cancer cell progression.