1. Gain of Glucose-Independent Growth upon Metastasis of Breast Cancer Cells to the Brain
- Author
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Lewis C. Cantley, Sun Jin Kim, Guang Gao, Jason W. Locasale, Yan Wang, Zhang Weihua, Tamar Melman, Lei Huo, Xuefeng Wu, John M. Asara, Jinyu Chen, James M. Briggs, Lei Xu, Fei Su, Ho Jeong Lee, Junqing He, Lakshmi Reddy Bollu, Isaiah J. Fidler, and Xiaojing Liu
- Subjects
Cancer Research ,medicine.medical_specialty ,Cell Survival ,Breast Neoplasms ,Biology ,Mass Spectrometry ,Article ,Metastasis ,Mice ,chemistry.chemical_compound ,Breast cancer ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,Gene silencing ,Gene Silencing ,Amino Acids ,RNA, Small Interfering ,Cell Proliferation ,Mice, Inbred BALB C ,Glycogen ,Brain Neoplasms ,Brain ,Cancer ,medicine.disease ,Fructose-Bisphosphatase ,Oxygen ,Glutamine ,Glucose ,Endocrinology ,Oncology ,chemistry ,Cancer cell ,Cancer research ,Female ,Glycolysis ,Brain metastasis - 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. Cancer Res; 75(3); 554–65. ©2014 AACR.
- Published
- 2015