A metabolic prosurvival role for PML in breast cancer
Arkaitz Carracedo, … , Zachary T. Schafer, Pier P. Pandolfi
Arkaitz Carracedo, … , Zachary T. Schafer, Pier P. Pandolfi
Published August 13, 2012
Citation Information: J Clin Invest. 2012;122(9):3088-3100. https://doi.org/10.1172/JCI62129.
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Research Article Oncology

A metabolic prosurvival role for PML in breast cancer

Abstract

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.

Authors

Arkaitz Carracedo, Dror Weiss, Amy K. Leliaert, Manoj Bhasin, Vincent C.J. de Boer, Gaelle Laurent, Andrew C. Adams, Maria Sundvall, Su Jung Song, Keisuke Ito, Lydia S. Finley, Ainara Egia, Towia Libermann, Zachary Gerhart-Hines, Pere Puigserver, Marcia C. Haigis, Elefteria Maratos-Flier, Andrea L. Richardson, Zachary T. Schafer, Pier P. Pandolfi

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Figure 7

PML overexpression correlates with reduced disease-free survival and poor prognosis in breast cancer.

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PML overexpression correlates with reduced disease-free survival and poo...
(A) Time to recurrence in the group of patients harboring PML-expressing vs. nonexpressing tumors. P value indicates the statistical significance by log-rank (Mantel-Cox) test. (B) GSEA analysis in PML-expressing vs. nonexpressing tumors shows a significant enrichment in poor-prognosis signature in PML-expressing tumors and a good-prognosis signature in nonexpressing tumors using the signature defined by van ‘t Veer et al. (60). The enrichment is depicted by nominal P value and NES. (C) GSEA analysis in PML-expressing vs. nonexpressing tumors shows a significant enrichment in activated Ppara signaling (top 500 Ppara-KO downregulated genes) in PML-expressing tumors. The enrichment is depicted by nominal P value and NES. (D) Schematic representation summarizing the main findings in this study. Briefly, PML increases the fraction of deacetylated PGC1A (AcPGC1A and PGC1A represent the acetylated and deacetylated portion of the protein, respectively) and leads to the activation of PPAR signaling and FAO. In turn, FAO increases ATP levels and promotes cell survival and luminal filling in breast cancer, indicating that in these conditions, PML provides a selective advantage in breast cancer.