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 1

PML regulates FAO and predisposition to obesity.

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PML regulates FAO and predisposition to obesity. (A–C) FAO levels in Pml...
(A–C) FAO levels in Pml-WT and -KO primary MEFs (A, n = 3) and primary hepatocytes (B, 4–5 independent hepatocyte cultures) and in HepG2 cells acutely infected with an empty or a PML-expressing retrovirus (C, from 2 independent infections; FAO was measured in triplicate for each infection. Representative Western blot for PML overexpression is shown). Etomoxir 100 μM. Representative experiments are shown. (D) FAO levels in HepG2 cells treated with vehicle or ATO (1 μM) for 72 hours (n = 4, a representative experiment is shown, right panel indicates PML levels [anti-PML] by Western blot using β-actin as endogenous control). (E–I) Body weight (E), fat mass (F), lean mass (G), GTT (H), and serum leptin levels (I) in Pml-WT (black bars/symbols) and Pml-KO (red bars/symbols) mice subjected to a control (LF) or HFD (HF) (n = 8). (J) Body weight in Pml-WT and Pml-KO LepOb/Ob female mice of the indicated age. *P < 0.05. Error bars in A–D represent mean ± SD; error bars in E–G represent mean ± SEM.