PPARα and PPARβ Are Differentially Affected by Ethanol and the Ethanol Metabolite Acetaldehyde in the MCF-7 Breast Cancer Cell Line

The activity and/or the level of the peroxisome proliferator-activated receptors (PPARs) in liver and oligodendrocytes are regulated by ethanol. Despite the association between ethanol consumption and breast cancer risk, and the increasing evidence for an involvement of PPARs in some cancers, there have been no studies on the effect of ethanol or its metabolite acetaldehyde on PPARs in breast cancer. Using the MCF-7 breast cancer cell line, we examined the relationship between ethanol and its metabolite acetaldehyde on PPAR alpha and PPAR beta transactivation. Ethanol (20mM) reduced the potency of the PPAR beta ligand GW0742, evident by a rightward shift in the GW0742 dose-response curve, whereas for PPAR alpha activation by GW7647, ethanol mediated its effects primarily through reducing efficacy as evidenced by a reduction in maximal response. Using the enzyme inhibitors 4-methylpyrazole and cyanamide and the metabolite acetaldehyde, we showed that PPAR alpha and PPAR beta are differentially modulated by ethanol and acetaldehyde. While acetaldehyde is responsible for the inhibition of PPAR alpha ligand inhibition with a concentration that inhibits 50% of activity (IC50) of 111 nM, acetaldehyde has no effect on PPAR beta or its ligand activation. Instead, inhibition of PPAR beta transactivation is mediated directly by ethanol. The differential effect of ethanol and acetaldehyde on PPAR alpha and PPAR beta further underscores the differences between these receptors and may indicate the relevance of PPARs in the effects of ethanol in the human breast.