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Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer.
Humphries, Brock A; Cutter, Alyssa C; Buschhaus, Johanna M; Chen, Yu-Chih; Qyli, Tonela; Palagama, Dilrukshika S W; Eckley, Samantha; Robison, Tanner H; Bevoor, Avinash; Chiang, Benjamin; Haley, Henry R; Sahoo, Saswat; Spinosa, Phillip C; Neale, Dylan B; Boppisetti, Jagadish; Sahoo, Debashis; Ghosh, Pradipta; Lahann, Joerg; Ross, Brian D; Yoon, Eusik; Luker, Kathryn E; Luker, Gary D.
Afiliación
  • Humphries BA; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Cutter AC; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Buschhaus JM; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Chen YC; Department of Biomedical Engineering, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Qyli T; Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA.
  • Palagama DSW; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • Eckley S; Forbes Institute for Cancer Discovery, University of Michigan, Ann Arbor, MI, USA.
  • Robison TH; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Bevoor A; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Chiang B; Unit for Laboratory Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Haley HR; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Sahoo S; Department of Biomedical Engineering, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Spinosa PC; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Neale DB; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Boppisetti J; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Sahoo D; Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA.
  • Ghosh P; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • Lahann J; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • Ross BD; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
  • Yoon E; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
  • Luker KE; Department of Pediatrics, Department of Computer Science and Engineering, Jacob's School of Engineering, Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • Luker GD; Department of Medicine, Department of Cellular and Molecular Medicine, Rebecca and John Moore Comprehensive Cancer Center, Veterans Affairs Medical Center, University of California San Diego, La Jolla, CA, USA.
Breast Cancer Res ; 22(1): 60, 2020 06 05.
Article en En | MEDLINE | ID: mdl-32503622
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Transformación Celular Neoplásica / Dinámicas Mitocondriales / Neoplasias de la Mama Triple Negativas / Mitocondrias Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Breast Cancer Res Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Transformación Celular Neoplásica / Dinámicas Mitocondriales / Neoplasias de la Mama Triple Negativas / Mitocondrias Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Breast Cancer Res Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos