title: The mitochondrial calcium uniporter regulates breast cancer progression via HIF-1α.
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.
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Tosatto
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sommaggio
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Saarland University, Homburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Kummerow
authors.affiliation: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Bentham
authors.affiliation: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Blacker
authors.affiliation: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors.forename: Tunde
authors.initials: T
authors.lastname: Berecz
authors.affiliation: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Saarland University, Homburg, Germany.
authors.forename: Ivan
authors.identifier: 0000-0001-9879-7174
authors.initials: I
authors.lastname: Bogeski
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Szabadkai
authors.affiliation: 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.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy rosario.rizzuto@unipd.it cristina.mammucari@unipd.it.
authors.forename: Cristina
authors.identifier: 0000-0003-3220-9610
authors.initials: C
authors.lastname: Mammucari
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D020868:Gene Silencing; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*
chemical_list: D015220:Calcium Channels; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C034703:mitochondrial calcium uniporter
keywords: HIF‐1α; breast cancer; metastasis; mitochondrial Ca2+ uptake; reactive oxygen species