title: PGC-1α supports glutamine metabolism in breast cancer.
abstract: BACKGROUND
  Glutamine metabolism is a central metabolic pathway in cancer. Recently, reductive carboxylation of glutamine for lipogenesis has been shown to constitute a key anabolic route in cancer cells. However, little is known regarding central regulators of the various glutamine metabolic pathways in cancer cells.
  
  
  METHODS
  The impact of PGC-1α and ERRα on glutamine enzyme expression was assessed in ERBB2+ breast cancer cell lines with quantitative RT-PCR, chromatin immunoprecipitation, and immunoblotting experiments. Glutamine flux was quantified using 13C-labeled glutamine and GC/MS analyses. Functional assays for lipogenesis were performed using 14C-labeled glutamine. The expression of glutamine metabolism genes in breast cancer patients was determined by bioinformatics analyses using The Cancer Genome Atlas.
  
  
  RESULTS
  We show that the transcriptional coactivator PGC-1α, along with the transcription factor ERRα, is a positive regulator of the expression of glutamine metabolism genes in ERBB2+ breast cancer. Indeed, ERBB2+ breast cancer cells with increased expression of PGC-1α display elevated expression of glutamine metabolism genes. Furthermore, ERBB2+ breast cancer cells with reduced expression of PGC-1α or when treated with C29, a pharmacological inhibitor of ERRα, exhibit diminished expression of glutamine metabolism genes. The biological relevance of the control of glutamine metabolism genes by the PGC-1α/ERRα axis is demonstrated by consequent regulation of glutamine flux through the citric acid cycle. PGC-1α and ERRα regulate both the canonical citric acid cycle (forward) and the reductive carboxylation (reverse) fluxes; the latter can be used to support de novo lipogenesis reactions, most notably in hypoxic conditions. Importantly, murine and human ERBB2+ cells lines display a significant dependence on glutamine availability for their growth. Finally, we show that PGC-1α expression is positively correlated with that of the glutamine pathway in ERBB2+ breast cancer patients, and high expression of this pathway is associated with reduced patient survival.
  
  
  CONCLUSIONS
  These data reveal that the PGC-1α/ERRα axis is a central regulator of glutamine metabolism in ERBB2+ breast cancer. This novel regulatory link, as well as the marked reduction in patient survival time associated with increased glutamine pathway gene expression, suggests that targeting glutamine metabolism may have therapeutic potential in the treatment of ERBB2+ breast cancer.
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.|Department of Biochemistry, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: McGuirk
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.|Department of Biochemistry, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
authors.forename: Simon-Pierre
authors.initials: SP
authors.lastname: Gravel
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.|Department of Biochemistry, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Deblois
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.|Department of Biochemistry, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Papadopoli
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.|Department of Physiology, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
authors.forename: Brandon
authors.initials: B
authors.lastname: Faubert
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts-Fourneaux, Esch-Belval L-4362, Luxembourg.
authors.forename: André
authors.initials: A
authors.lastname: Wegner
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts-Fourneaux, Esch-Belval L-4362, Luxembourg.
authors.forename: Karsten
authors.initials: K
authors.lastname: Hiller
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.|Metabolomics Core Facility, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.affiliation: Department of Biochemistry, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.|Department of Biological Sciences, Columbia University, 1212 Amsterdam Ave, New York, NY 10027, USA.|Center for Computational Biology and Bioinformatics, Columbia University Medical Center, 1130 St. Nicholas Ave, New York, NY 10032, USA.
authors.forename: Uri David
authors.initials: UD
authors.lastname: Akavia
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.|Department of Physiology, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.|Department of Biochemistry, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.|Department of Biochemistry, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre