Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis

Nat Commun. 2021 Dec 15;12(1):7311. doi: 10.1038/s41467-021-27559-z.

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.

Trial registration: ClinicalTrials.gov NCT00195091.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Copper / metabolism*
  • Copper Transport Proteins / genetics
  • Copper Transport Proteins / metabolism
  • Female
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Neoplasm Metastasis
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Oxidative Phosphorylation
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology

Substances

  • COX17 protein, human
  • Copper Transport Proteins
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Copper
  • Mechanistic Target of Rapamycin Complex 1

Associated data

  • ClinicalTrials.gov/NCT00195091