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Cancer Res. 2015 Feb 1;75(3):554-65. doi: 10.1158/0008-5472.CAN-14-2268. Epub 2014 Dec 15.

Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain.

Author information

1
Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas.
2
Department of Cancer Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
3
Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
4
Division of Nutritional Sciences, Cornell University, Ithaca, New York.
5
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School Boston, Massachusetts.
6
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.
7
Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
8
Department of Biochemistry and Biology, College of Natural Science and Mathematics, University of Houston, Houston, Texas. wzhang13@uh.edu.

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.

PMID:
25511375
PMCID:
PMC4315743
DOI:
10.1158/0008-5472.CAN-14-2268
[Indexed for MEDLINE]
Free PMC Article

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