Zachary T. Schafer

Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted as both a negative regulator of PPARγ coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated 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 fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment.

In this issue of the JCI, two reports provide intriguing new information on the role of the inflammatory cytokine IL-6 in breast and lung cancer. The study by Sansone et al. implicates IL-6 in the instigation of malignant properties in breast cancer stem cells (see the related article beginning on page 3988). The study by Gao et al. identifies mutant variants of EGFR as inducers of IL-6 in lung adenocarcinomas (see the related article beginning on page 3846). These studies add to our understanding of potential roles for IL-6 in cancer and further motivate investigations of IL-6-targeted chemotherapeutics.