Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer
Abstract Background Mitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment. Current research presents conflicting evidence for functions of mitochondrial fission and fusion in tumor progression. Here, we investigated how mitochondrial fission and fus...
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BMC
2020-06-01
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| Series: | Breast Cancer Research |
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| Online Access: | http://link.springer.com/article/10.1186/s13058-020-01301-x |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Brock A. Humphries Alyssa C. Cutter Johanna M. Buschhaus Yu-Chih Chen Tonela Qyli Dilrukshika S. W. Palagama Samantha Eckley Tanner H. Robison Avinash Bevoor Benjamin Chiang Henry R. Haley Saswat Sahoo Phillip C. Spinosa Dylan B. Neale Jagadish Boppisetti Debashis Sahoo Pradipta Ghosh Joerg Lahann Brian D. Ross Eusik Yoon Kathryn E. Luker Gary D. Luker |
| spellingShingle |
Brock A. Humphries Alyssa C. Cutter Johanna M. Buschhaus Yu-Chih Chen Tonela Qyli Dilrukshika S. W. Palagama Samantha Eckley Tanner H. Robison Avinash Bevoor Benjamin Chiang Henry R. Haley Saswat Sahoo Phillip C. Spinosa Dylan B. Neale Jagadish Boppisetti Debashis Sahoo Pradipta Ghosh Joerg Lahann Brian D. Ross Eusik Yoon Kathryn E. Luker Gary D. Luker Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer Breast Cancer Research Triple-negative breast cancer ERK Akt Fluorescence microscopy Mitochondrial fission Mitochondrial fusion |
| author_facet |
Brock A. Humphries Alyssa C. Cutter Johanna M. Buschhaus Yu-Chih Chen Tonela Qyli Dilrukshika S. W. Palagama Samantha Eckley Tanner H. Robison Avinash Bevoor Benjamin Chiang Henry R. Haley Saswat Sahoo Phillip C. Spinosa Dylan B. Neale Jagadish Boppisetti Debashis Sahoo Pradipta Ghosh Joerg Lahann Brian D. Ross Eusik Yoon Kathryn E. Luker Gary D. Luker |
| author_sort |
Brock A. Humphries |
| title |
Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer |
| title_short |
Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer |
| title_full |
Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer |
| title_fullStr |
Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer |
| title_full_unstemmed |
Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer |
| title_sort |
enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer |
| publisher |
BMC |
| series |
Breast Cancer Research |
| issn |
1465-542X |
| publishDate |
2020-06-01 |
| description |
Abstract Background Mitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment. Current research presents conflicting evidence for functions of mitochondrial fission and fusion in tumor progression. Here, we investigated how mitochondrial fission and fusion states regulate underlying processes of cancer progression and metastasis in triple-negative breast cancer (TNBC). Methods We enforced mitochondrial fission and fusion states through chemical or genetic approaches and measured migration and invasion of TNBC cells in 2D and 3D in vitro models. We also utilized kinase translocation reporters (KTRs) to identify single cell effects of mitochondrial state on signaling cascades, PI3K/Akt/mTOR and Ras/Raf/MEK/ERK, commonly activated in TNBC. Furthermore, we determined effects of fission and fusion states on metastasis, bone destruction, and signaling in mouse models of breast cancer. Results Enforcing mitochondrial fission through chemical or genetic approaches inhibited migration, invasion, and metastasis in TNBC. Breast cancer cells with predominantly fissioned mitochondria exhibited reduced activation of Akt and ERK both in vitro and in mouse models of breast cancer. Treatment with leflunomide, a potent activator of mitochondrial fusion proteins, overcame inhibitory effects of fission on migration, signaling, and metastasis. Mining existing datasets for breast cancer revealed that increased expression of genes associated with mitochondrial fission correlated with improved survival in human breast cancer. Conclusions In TNBC, mitochondrial fission inhibits cellular processes and signaling pathways associated with cancer progression and metastasis. These data suggest that therapies driving mitochondrial fission may benefit patients with breast cancer. |
| topic |
Triple-negative breast cancer ERK Akt Fluorescence microscopy Mitochondrial fission Mitochondrial fusion |
| url |
http://link.springer.com/article/10.1186/s13058-020-01301-x |
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doaj-9c69e5ad28e54a34b582b8df084a9f782021-04-02T15:24:21ZengBMCBreast Cancer Research1465-542X2020-06-0122111810.1186/s13058-020-01301-xEnhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancerBrock A. Humphries0Alyssa C. Cutter1Johanna M. Buschhaus2Yu-Chih Chen3Tonela Qyli4Dilrukshika S. W. Palagama5Samantha Eckley6Tanner H. Robison7Avinash Bevoor8Benjamin Chiang9Henry R. Haley10Saswat Sahoo11Phillip C. Spinosa12Dylan B. Neale13Jagadish Boppisetti14Debashis Sahoo15Pradipta Ghosh16Joerg Lahann17Brian D. Ross18Eusik Yoon19Kathryn E. Luker20Gary D. Luker21Center for Molecular Imaging, Department of Radiology, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganDepartment of Electrical Engineering and Computer Science, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganUnit for Laboratory Medicine, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganDepartment of Electrical Engineering and Computer Science, University of MichiganDepartment of Chemical Engineering, University of MichiganDepartment of Chemical Engineering, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganDepartment of Pediatrics, Department of Computer Science and Engineering, Jacob’s School of Engineering, Rebecca and John Moore Comprehensive Cancer Center, University of California San DiegoDepartment of Medicine, Department of Cellular and Molecular Medicine, Rebecca and John Moore Comprehensive Cancer Center, Veterans Affairs Medical Center, University of California San DiegoBiointerfaces Institute, Departments of Chemical Engineering, Materials Science and Engineering, Biomedical Engineering, and Macromolecular Science and Engineering, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganDepartment of Biomedical Engineering, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganCenter for Molecular Imaging, Department of Radiology, University of MichiganAbstract Background Mitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment. Current research presents conflicting evidence for functions of mitochondrial fission and fusion in tumor progression. Here, we investigated how mitochondrial fission and fusion states regulate underlying processes of cancer progression and metastasis in triple-negative breast cancer (TNBC). Methods We enforced mitochondrial fission and fusion states through chemical or genetic approaches and measured migration and invasion of TNBC cells in 2D and 3D in vitro models. We also utilized kinase translocation reporters (KTRs) to identify single cell effects of mitochondrial state on signaling cascades, PI3K/Akt/mTOR and Ras/Raf/MEK/ERK, commonly activated in TNBC. Furthermore, we determined effects of fission and fusion states on metastasis, bone destruction, and signaling in mouse models of breast cancer. Results Enforcing mitochondrial fission through chemical or genetic approaches inhibited migration, invasion, and metastasis in TNBC. Breast cancer cells with predominantly fissioned mitochondria exhibited reduced activation of Akt and ERK both in vitro and in mouse models of breast cancer. Treatment with leflunomide, a potent activator of mitochondrial fusion proteins, overcame inhibitory effects of fission on migration, signaling, and metastasis. Mining existing datasets for breast cancer revealed that increased expression of genes associated with mitochondrial fission correlated with improved survival in human breast cancer. Conclusions In TNBC, mitochondrial fission inhibits cellular processes and signaling pathways associated with cancer progression and metastasis. These data suggest that therapies driving mitochondrial fission may benefit patients with breast cancer.http://link.springer.com/article/10.1186/s13058-020-01301-xTriple-negative breast cancerERKAktFluorescence microscopyMitochondrial fissionMitochondrial fusion |