PML regulates PPAR signaling and fatty acid oxidation in breast cancer. Mus musculus

Cancer cells exhibit an aberrant metabolism which facilitates more efficient production of biomass, and hence tumor growth and progression. The genetic cues modulating this metabolic switch remain largely undetermined, however. Here we identify a metabolic function for PML which reveals an unexpected role for this bona-fide tumor suppressor in pro-survival activity in breast cancer. We find that PML acts as both a negative regulator of PGC1A acetylation and as a potent activator of peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid oxidation (FAO). We further show that as FAO PML promotes ATP production, inhibits anoikis, and allows luminal filling in 3D basement membrane breast culture models. Furthermore, analysis of breast cancer biopsies reveals that PML is over-expressed in a subset of breast cancers, and is enriched in triple-negative cases. Indeed, PML expression in breast cancer correlates strikingly with reduced time to recurrence, a gene signature of poor prognosis and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in FAO metabolism are amenable to pharmacological suppression as a mode of cancer prevention and treatment. Overall design: Mouse livers from Pml-WT and Pml-KO mice were harvested after 20 week diet with high fat diet (60% Cal from fat; Harlan 06414) or control diet (10% Cal from fat; Harlan 08806). Mice were fasted for 8h prior to tissue harvesting in order to avoid the effect of immediate food intake. 3 tissue extracts per genotype and condition were analyzed (out of a total of 8 mice per group).