title: Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate.
abstract: OBJECTIVE
  Glutamine addiction in c-MYC-overexpressing breast cancer is targeted by the aminotransferase inhibitor, aminooxyacetate (AOA). However, the mechanism of ensuing cell death remains unresolved.
  
  
  METHODS
  A correlation between glutamine dependence for growth and c-MYC expression was studied in breast cancer cell lines. The cytotoxic effects of AOA, its correlation with high c-MYC expression, and effects on enzymes in the glutaminolytic pathway were investigated. AOA-induced cell death was assessed by measuring changes in metabolite levels by magnetic resonance spectroscopy (MRS), the effects of amino acid depletion on nucleotide synthesis by cell-cycle and bromodeoxyuridine (BrdUrd) uptake analysis, and activation of the endoplasmic reticulum (ER) stress-mediated pathway. Antitumor effects of AOA with or without common chemotherapies were determined in breast cancer xenografts in immunodeficient mice and in a transgenic MMTV-rTtA-TetO-myc mouse mammary tumor model.
  
  
  RESULTS
  We established a direct correlation between c-MYC overexpression, suppression of glutaminolysis, and AOA sensitivity in most breast cancer cells. MRS, cell-cycle analysis, and BrdUrd uptake measurements indicated depletion of aspartic acid and alanine leading to cell-cycle arrest at S-phase by AOA. Activation of components of the ER stress-mediated pathway, initiated through GRP78, led to apoptotic cell death. AOA inhibited growth of SUM159, SUM149, and MCF-7 xenografts and c-myc-overexpressing transgenic mouse mammary tumors. In MDA-MB-231, AOA was effective only in combination with chemotherapy.
  
  
  CONCLUSIONS
  AOA mediates its cytotoxic effects largely through the stress response pathway. The preclinical data of AOA's effectiveness provide a strong rationale for further clinical development, particularly for c-MYC-overexpressing breast cancers.
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Preethi
authors: P
authors: Korangath
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Wei Wen
authors: WW
authors: Teo
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Helen
authors: H
authors: Sadik
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Liangfeng
authors: L
authors: Han
authors: Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Noriko
authors: N
authors: Mori
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Charlotte M
authors: CM
authors: Huijts
authors: Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Flonne
authors: F
authors: Wildes
authors: Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Santosh
authors: S
authors: Bharti
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Zhe
authors: Z
authors: Zhang
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Cesar A
authors: CA
authors: Santa-Maria
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Hualing
authors: H
authors: Tsai
authors: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors: Chi V
authors: CV
authors: Dang
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Vered
authors: V
authors: Stearns
authors: Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Zaver M
authors: ZM
authors: Bhujwalla
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. saras@jhmi.edu.
authors: Saraswati
authors: S
authors: Sukumar
mesh_terms: D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D005973:Glutamine; D000625:Aminooxyacetic Acid