Open AccessThe mitochondrial calcium uniporter regulates breast cancer progression via HIF ‐1α
Author(s) -
Tosatto Anna,
Sommaggio Roberta,
Kummerow Carsten,
Bentham Robert B,
Blacker Thomas S,
Berecz Tunde,
Duchen Michael R,
Rosato Antonio,
Bogeski Ivan,
Szabadkai Gyorgy,
Rizzuto Rosario,
Mammucari Cristina
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606255
Subject(s) - uniporter , cancer research , triple negative breast cancer , metastasis , downregulation and upregulation , biology , mitochondrion , breast cancer , chemistry , microbiology and biotechnology , cancer , biochemistry , cytosol , enzyme , genetics , gene
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.