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...
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| Format: | Article |
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Springer Nature
2016-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606255 |
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| author | Anna Tosatto Roberta Sommaggio Carsten Kummerow Robert B Bentham Thomas S Blacker Tunde Berecz Michael R Duchen Antonio Rosato Ivan Bogeski Gyorgy Szabadkai Rosario Rizzuto Cristina Mammucari |
| author_facet | Anna Tosatto Roberta Sommaggio Carsten Kummerow Robert B Bentham Thomas S Blacker Tunde Berecz Michael R Duchen Antonio Rosato Ivan Bogeski Gyorgy Szabadkai Rosario Rizzuto Cristina Mammucari |
| author_sort | Anna Tosatto |
| collection | DOAJ |
| description | 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 Ca2+ uptake, correlates with tumor size and lymph node infiltration, suggesting that mitochondrial Ca2+ 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 Ca2+. 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 Ca2+ uptake is a potential novel therapeutic target for clinical intervention. |
| format | Article |
| id | doaj-art-772fae7597ff450391056d14ec5509ff |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-772fae7597ff450391056d14ec5509ff2025-08-20T03:42:52ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-04-018556958510.15252/emmm.201606255The mitochondrial calcium uniporter regulates breast cancer progression via HIF‐1αAnna Tosatto0Roberta Sommaggio1Carsten Kummerow2Robert B Bentham3Thomas S Blacker4Tunde Berecz5Michael R Duchen6Antonio Rosato7Ivan Bogeski8Gyorgy Szabadkai9Rosario Rizzuto10Cristina Mammucari11Department of Biomedical Sciences, University of PaduaDepartment of Surgery, Oncology and Gastroenterology, University of PaduaDepartment of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Saarland UniversityDepartment of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College LondonDepartment of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College LondonDepartment of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College LondonDepartment of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College LondonDepartment of Surgery, Oncology and Gastroenterology, University of PaduaDepartment of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Saarland UniversityDepartment of Biomedical Sciences, University of PaduaDepartment of Biomedical Sciences, University of PaduaDepartment of Biomedical Sciences, University of PaduaAbstract 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 Ca2+ uptake, correlates with tumor size and lymph node infiltration, suggesting that mitochondrial Ca2+ 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 Ca2+. 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 Ca2+ uptake is a potential novel therapeutic target for clinical intervention.https://doi.org/10.15252/emmm.201606255breast cancerHIF‐1αmetastasismitochondrial Ca2+ uptakereactive oxygen species |
| spellingShingle | Anna Tosatto Roberta Sommaggio Carsten Kummerow Robert B Bentham Thomas S Blacker Tunde Berecz Michael R Duchen Antonio Rosato Ivan Bogeski Gyorgy Szabadkai Rosario Rizzuto Cristina Mammucari The mitochondrial calcium uniporter regulates breast cancer progression via HIF‐1α EMBO Molecular Medicine breast cancer HIF‐1α metastasis mitochondrial Ca2+ uptake reactive oxygen species |
| title | The mitochondrial calcium uniporter regulates breast cancer progression via HIF‐1α |
| title_full | The mitochondrial calcium uniporter regulates breast cancer progression via HIF‐1α |
| title_fullStr | The mitochondrial calcium uniporter regulates breast cancer progression via HIF‐1α |
| title_full_unstemmed | The mitochondrial calcium uniporter regulates breast cancer progression via HIF‐1α |
| title_short | The mitochondrial calcium uniporter regulates breast cancer progression via HIF‐1α |
| title_sort | mitochondrial calcium uniporter regulates breast cancer progression via hif 1α |
| topic | breast cancer HIF‐1α metastasis mitochondrial Ca2+ uptake reactive oxygen species |
| url | https://doi.org/10.15252/emmm.201606255 |
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