title: Adaptation of energy metabolism in breast cancer brain metastases.
abstract: Brain metastases are among the most feared complications in breast cancer, as no therapy exists that prevents or eliminates breast cancer spreading to the brain. New therapeutic strategies depend on specific knowledge of tumor cell properties that allow breast cancer cell growth within the brain tissue. To provide information in this direction, we established a human breast cancer cell model for brain metastasis based on circulating tumor cells from a breast cancer patient and variants of these cells derived from bone or brain lesions in immunodeficient mice. The brain-derived cells showed an increased potential for brain metastasis in vivo and exhibited a unique protein expression profile identified by large-scale proteomic analysis. This protein profile is consistent with either a selection of predisposed cells or bioenergetic adaptation of the tumor cells to the unique energy metabolism of the brain. Increased expression of enzymes involved in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation pathways suggests that the brain metastatic cells derive energy from glucose oxidation. The cells further showed enhanced activation of the pentose phosphate pathway and the glutathione system, which can minimize production of reactive oxygen species resulting from an enhanced oxidative metabolism. These changes promoted resistance of brain metastatic cells to drugs that affect the cellular redox balance. Importantly, the metabolic alterations are associated with strongly enhanced tumor cell survival and proliferation in the brain microenvironment. Thus, our data support the hypothesis that predisposition or adaptation of the tumor cell energy metabolism is a key element in breast cancer brain metastasis, and raise the possibility of targeting the functional differentiation in breast cancer brain lesions as a novel therapeutic strategy.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. emilyc@scripps.edu
authors.forename: Emily I
authors.initials: EI
authors.lastname: Chen
authors.forename: Johannes
authors.initials: J
authors.lastname: Hewel
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Krueger
authors.forename: Claire
authors.initials: C
authors.lastname: Tiraby
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weber
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kralli
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Felding-Habermann
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D002952:Citric Acid Cycle; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010427:Pentose Phosphate Pathway; D040901:Proteomics
chemical_list: D005978:Glutathione