1. Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis
- Author
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Ramchandani, Divya, Berisa, Mirela, Tavarez, Diamile A., Li, Zhuoning, Miele, Matthew, Bai, Yang, Lee, Sharrell B., Ban, Yi, Dephoure, Noah, Hendrickson, Ronald C., Cloonan, Suzanne M., Gao, Dingcheng, Cross, Justin R., Vahdat, Linda T., and Mittal, Vivek
- Subjects
Multidisciplinary ,SOXB1 Transcription Factors ,Science ,General Physics and Astronomy ,Triple Negative Breast Neoplasms ,General Chemistry ,Mechanistic Target of Rapamycin Complex 1 ,Cancer metabolism ,Article ,Oxidative Phosphorylation ,General Biochemistry, Genetics and Molecular Biology ,Mitochondria ,Mice, Inbred C57BL ,Mice ,Breast cancer ,Copper Transport Proteins ,Cell Line, Tumor ,Animals ,Humans ,Female ,Neoplasm Metastasis ,Octamer Transcription Factor-3 ,Copper - Abstract
Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression. The orally bioavailable copper chelating agent tetrathiomolybdate (TM) has been associated with a significant survival benefit in high-risk triple negative breast cancer (TNBC) patients. Despite these promising data, the mechanisms by which copper depletion impacts metastasis are poorly understood and this remains a major barrier to advancing TM to a randomized phase II trial. Here, using two independent TNBC models, we report a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit elevated intracellular copper levels and a marked sensitivity to TM. Global proteomic and metabolomic profiling identifies TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We also identify AMPK/mTORC1 energy sensor as an important downstream pathway and show that AMPK inhibition rescues TM-mediated loss of invasion. Furthermore, loss of the mitochondria-specific copper chaperone, COX17, restricts copper deficiency to mitochondria and phenocopies TM-mediated alterations. These findings identify a copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials., Copper depletion has been reported to improve survival in patients with triple negative breast cancer (TNBC) but the underlying mechanisms are not completely understood. Here, the authors show that copper chelation reduces mitochondrial oxidative phosphorylation leading to decreased TNBC metastasis.
- Published
- 2021