title: 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.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Harvard Medical School, and Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.forename: Dror
authors.initials: D
authors.lastname: Weiss
authors.forename: Amy K
authors.initials: AK
authors.lastname: Leliaert
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhasin
authors.forename: Vincent C J
authors.initials: VC
authors.lastname: de Boer
authors.forename: Gaelle
authors.initials: G
authors.lastname: Laurent
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.forename: Maria
authors.initials: M
authors.lastname: Sundvall
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Song
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ito
authors.forename: Lydia S
authors.initials: LS
authors.lastname: Finley
authors.forename: Ainara
authors.initials: A
authors.lastname: Egia
authors.forename: Towia
authors.initials: T
authors.lastname: Libermann
authors.forename: Zachary
authors.initials: Z
authors.lastname: Gerhart-Hines
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
authors.forename: Elefteria
authors.initials: E
authors.lastname: Maratos-Flier
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Schafer
authors.forename: Pier P
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000107:Acetylation; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D018572:Disease-Free Survival; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors; C485290:Ppargc1a protein, mouse; D000071156:Promyelocytic Leukemia Protein; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human