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Breast Cancer Research
Published in: Breast Cancer Research 1/2020

01-12-2020 | Metastasis | Research article

Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer

Authors: 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

Published in: Breast Cancer Research | Issue 1/2020

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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.
Appendix
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Metadata
Title
Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer
Authors
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
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01301-x

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