Format

Send to

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

The mitochondrial calcium uniporter regulates breast cancer progression via HIF-1α.

Author information

1
Department of Biomedical Sciences, University of Padua, Padua, Italy.
2
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
3
Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Saarland University, Homburg, Germany.
4
Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
5
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
6
Department of Biomedical Sciences, University of Padua, Padua, Italy Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
7
Department of Biomedical Sciences, University of Padua, Padua, Italy CNR Institute of Neuroscience, National Council of Research, Padua, Italy rosario.rizzuto@unipd.it cristina.mammucari@unipd.it.
8
Department of Biomedical Sciences, University of Padua, Padua, Italy rosario.rizzuto@unipd.it cristina.mammucari@unipd.it.

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

PMID:
27138568
PMCID:
PMC4864890
DOI:
10.15252/emmm.201606255
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center