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

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 - 2017/9/15

Y1 - 2017/9/15

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 ¼ 20) and healthy women (n ¼ 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 b-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.

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 ¼ 20) and healthy women (n ¼ 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 b-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.

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

SN - 0008-5472

VL - 77

SP - 4894

EP - 4904

JO - Cancer Research

JF - Cancer Research

IS - 18

ER -