Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development
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Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development. / Dethlefsen, Christine; Hansen, Louise S; Lillelund, Christian; Andersen, Christina; Gehl, Julie; Christensen, Jesper F; Pedersen, Bente K; Hojman, Pernille.
In: Cancer Research, Vol. 77, No. 18, 09.2017, p. 4894-4904.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development
AU - Dethlefsen, Christine
AU - Hansen, Louise S
AU - Lillelund, Christian
AU - Andersen, Christina
AU - Gehl, Julie
AU - Christensen, Jesper F
AU - Pedersen, Bente K
AU - Hojman, Pernille
N1 - ©2017 American Association for Cancer Research.
PY - 2017/9
Y1 - 2017/9
N2 - 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-Foxn1(nu) 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); 4894-904. ©2017 AACR.
AB - 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-Foxn1(nu) 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); 4894-904. ©2017 AACR.
KW - Adaptor Proteins, Signal Transducing
KW - Adolescent
KW - Adult
KW - Animals
KW - Apoptosis
KW - Biomarkers, Tumor
KW - Breast Neoplasms
KW - Case-Control Studies
KW - Catecholamines
KW - Cell Proliferation
KW - Exercise
KW - Female
KW - Follow-Up Studies
KW - Forkhead Transcription Factors
KW - Genes, Tumor Suppressor
KW - Humans
KW - Mice
KW - Phosphoproteins
KW - Physical Conditioning, Animal
KW - Protein-Serine-Threonine Kinases
KW - Tumor Cells, Cultured
KW - Young Adult
KW - Journal Article
U2 - 10.1158/0008-5472.CAN-16-3125
DO - 10.1158/0008-5472.CAN-16-3125
M3 - Journal article
C2 - 28887324
VL - 77
SP - 4894
EP - 4904
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 18
ER -
ID: 185712687