title: Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain.
abstract: Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells, but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the nonoxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBP) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients.
authors.affiliation: Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
authors.forename: Ho-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
authors.forename: Lei
authors.initials: L
authors.lastname: Huo
authors.affiliation: Department of Cancer Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
authors.forename: Junqing
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas.
authors.forename: Lakshmi R
authors.initials: LR
authors.lastname: Bollu
authors.affiliation: Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas.
authors.forename: Guang
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas.
authors.forename: Fei
authors.initials: F
authors.lastname: Su
authors.affiliation: Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas.
authors.forename: James
authors.initials: J
authors.lastname: Briggs
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School Boston, Massachusetts.
authors.forename: Tamar
authors.initials: T
authors.lastname: Melman
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Cancer Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Fidler
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas. wzhang13@uh.edu.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Weihua
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D006597:Fructose-Bisphosphatase / Q000235:genetics; D020868:Gene Silencing; D005947:Glucose / Q000737:chemistry*; D006003:Glycogen / Q000737:chemistry; D006019:Glycolysis; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D000596:Amino Acids; D034741:RNA, Small Interfering; D006003:Glycogen; D006597:Fructose-Bisphosphatase; D005947:Glucose; D010100:Oxygen