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Tumor and Stem Cell Biology

Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development

Christine Dethlefsen, Louise S. Hansen, Christian Lillelund, Christina Andersen, Julie Gehl, Jesper F. Christensen, Bente K. Pedersen and Pernille Hojman
Christine Dethlefsen
Centre of Inflammation and Metabolism (CIM) and Centre for Physical Activity Research (CFAS), Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark.
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Louise S. Hansen
Centre of Inflammation and Metabolism (CIM) and Centre for Physical Activity Research (CFAS), Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark.
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Christian Lillelund
The University Hospitals Centre for Health Research, Rigshospitalet, Copenhagen, Denmark.
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Christina Andersen
The University Hospitals Centre for Health Research, Rigshospitalet, Copenhagen, Denmark.
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Julie Gehl
Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
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Jesper F. Christensen
Centre of Inflammation and Metabolism (CIM) and Centre for Physical Activity Research (CFAS), Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark.
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Bente K. Pedersen
Centre of Inflammation and Metabolism (CIM) and Centre for Physical Activity Research (CFAS), Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark.
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Pernille Hojman
Centre of Inflammation and Metabolism (CIM) and Centre for Physical Activity Research (CFAS), Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark.Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
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  • For correspondence: phojman@inflammation-metabolism.dk
DOI: 10.1158/0008-5472.CAN-16-3125
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Abstract

Strong epidemiologic evidence documents the protective effect of physical activity on breast cancer risk, recurrence, and mortality, but the underlying mechanisms remain to be identified. Using human exercise–conditioned serum for breast cancer cell incubation studies and murine exercise interventions, we aimed to identify exercise factors and signaling pathways involved in the exercise-dependent suppression of breast cancer. Exercise-conditioned serum from both women with breast cancer (n = 20) and healthy women (n = 7) decreased MCF-7 (hormone-sensitive) and MDA-MB-231 (hormone-insensitive) breast cancer cell viability in vitro by 11% to 19% and reduced tumorigenesis by 50% when preincubated MCF-7 breast cancer cells were inoculated into NMRI-Foxn1nu mice. This exercise-mediated suppression of cell viability and tumor formation was completely blunted by blockade of β-adrenergic signaling in MCF-7 cells, indicating that catecholamines were the responsible exercise factors. Both epinephrine (EPI) and norepinephrine (NE) could directly inhibit breast cancer cell viability, as well as tumor growth in vivo. EPI and NE activate the tumor suppressor Hippo signaling pathway, and the suppressive effect of exercise-conditioned serum was found to be mediated through phosphorylation and cytoplasmic retention of YAP and reduced expression of downstream target genes, for example, ANKRD1 and CTGF. In parallel, tumor-bearing mice with access to running wheels showed reduced growth of MCF-7 (–36%, P < 0.05) and MDA-MB-231 (–66%, P < 0.01) tumors and, for the MCF-7 tumor, increased regulation of the Hippo signaling pathway. Taken together, our findings offer a mechanistic explanation for exercise-dependent suppression of breast cancer cell growth. Cancer Res; 77(18); 1–11. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received November 16, 2016.
  • Revision received April 19, 2017.
  • Accepted June 27, 2017.
  • ©2017 American Association for Cancer Research.
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Published OnlineFirst September 8, 2017
doi: 10.1158/0008-5472.CAN-16-3125

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Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development
Christine Dethlefsen, Louise S. Hansen, Christian Lillelund, Christina Andersen, Julie Gehl, Jesper F. Christensen, Bente K. Pedersen and Pernille Hojman
Cancer Res September 8 2017 DOI: 10.1158/0008-5472.CAN-16-3125

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Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development
Christine Dethlefsen, Louise S. Hansen, Christian Lillelund, Christina Andersen, Julie Gehl, Jesper F. Christensen, Bente K. Pedersen and Pernille Hojman
Cancer Res September 8 2017 DOI: 10.1158/0008-5472.CAN-16-3125
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