The Mitochondrial Calcium Uniporter Regulates Breast Cancer Progression via HIF-1α

EMBO Mol Med. 2016 May 2;8(5):569-85. doi: 10.15252/emmm.201606255. Print 2016 May.

Abstract

Triple-negative breast cancer (TNBC) represents the most aggressive breast tumor subtype. However, the molecular determinants responsible for the metastatic TNBC phenotype are only partially understood. We here show that expression of the mitochondrial calcium uniporter (MCU), the selective channel responsible for mitochondrial Ca(2+) uptake, correlates with tumor size and lymph node infiltration, suggesting that mitochondrial Ca(2+) uptake might be instrumental for tumor growth and metastatic formation. Accordingly, MCU downregulation hampered cell motility and invasiveness and reduced tumor growth, lymph node infiltration, and lung metastasis in TNBC xenografts. In MCU-silenced cells, production of mitochondrial reactive oxygen species (mROS) is blunted and expression of the hypoxia-inducible factor-1α (HIF-1α) is reduced, suggesting a signaling role for mROS and HIF-1α, downstream of mitochondrial Ca(2+) Finally, in breast cancer mRNA samples, a positive correlation of MCU expression with HIF-1α signaling route is present. Our results indicate that MCU plays a central role in TNBC growth and metastasis formation and suggest that mitochondrial Ca(2+) uptake is a potential novel therapeutic target for clinical intervention.

Keywords: HIF‐1α; breast cancer; metastasis; mitochondrial Ca2+ uptake; reactive oxygen species.

Publication types

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

MeSH terms

  • Animals
  • Calcium Channels / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Female
  • Gene Silencing
  • Heterografts
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice, SCID
  • Neoplasm Invasiveness*
  • Neoplasm Metastasis / pathology*
  • Reactive Oxygen Species / metabolism
  • Triple Negative Breast Neoplasms / pathology*

Substances

  • Calcium Channels
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Reactive Oxygen Species
  • mitochondrial calcium uniporter