No Evidence for Effect of Exercise on Transcriptome of NK Cells in Breast Cancer Patients Undergoing Adjuvant Therapy: Results From a Pilot Study

Background Mobilization and activation of natural killer cells (NK cells) have been hypothesized to contribute to observed protective effects of exercise on cancer development and progression. Some evidence exists for acute effects of aerobic exercise on NK cell mobilization and function, i.e., alteration of the gene expression profile of NK cells. Yet, the chronic effects of exercise training, and effects of other modalities than endurance exercise are still understudied. Here, we investigated the chronic effects of a 12-week resistance exercise program on NK cell gene expression in breast cancer patients undergoing adjuvant chemo- or radiotherapy. Methods Breast cancer patients were randomly assigned to either a 12-week resistance exercise program or a relaxation control group concomitant to adjuvant therapy. In a subsample of 19 participants, RNA was extracted from magnet bead isolated NK cells and subsequently analyzed for differential gene expression using microarray Illumina HumanHT-12 v4 before and after the intervention. Results After chronic exercise intervention several genes showed higher differential expression compared to the control group. However, after correction for multiple testing, baseline-adjusted analyses of covariance indicated no significant differences between the intervention and the control group with regard to the gene expression profile. Discussion Our findings suggest that 12-week resistance-exercise did not alter the gene expression profile of NK cells in breast cancer patients undergoing adjuvant therapy on the long term. Further studies with larger sample sizes and specifically designed to investigate whether exercise-induced changes in NK cell function are attributed to acute effects are warranted.

[1]  R. Schier,et al.  Acute Exercise Increases the Expression of KIR2DS4 by Promoter Demethylation in NK Cells , 2018, International Journal of Sports Medicine.

[2]  P. Gordon,et al.  Immune adaptation to chronic intense exercise training: new microarray evidence , 2017, BMC Genomics.

[3]  I. Nookaew,et al.  Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution. , 2016, Cell metabolism.

[4]  C. Ulrich,et al.  Effects of resistance exercise on fatigue and quality of life in breast cancer patients undergoing adjuvant chemotherapy: A randomized controlled trial , 2015, International journal of cancer.

[5]  E. Zopf,et al.  Exercise-induced Natural Killer Cell Activation is Driven by Epigenetic Modifications , 2015, International Journal of Sports Medicine.

[6]  T. Nyman,et al.  OSBP-related protein 3 (ORP3) coupling with VAMP-associated protein A regulates R-Ras activity. , 2015, Experimental cell research.

[7]  J. Krieger,et al.  PBMCs express a transcriptome signature predictor of oxygen uptake responsiveness to endurance exercise training in men. , 2015, Physiological genomics.

[8]  B. Bodai,et al.  Breast cancer survivorship: a comprehensive review of long-term medical issues and lifestyle recommendations. , 2015, The Permanente journal.

[9]  A. Mierau,et al.  Impact of exercise on pro inflammatory cytokine levels and epigenetic modulations of tumor‐competitive lymphocytes in Non‐Hodgkin‐Lymphoma patients‐randomized controlled trial , 2014, European journal of haematology.

[10]  N. Habermann,et al.  Randomized, controlled trial of resistance training in breast cancer patients receiving adjuvant radiotherapy: results on cancer-related fatigue and quality of life. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  K. Shirahige,et al.  5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex. , 2014, Cell reports.

[12]  P. Basse,et al.  NK cells in the tumor microenvironment. , 2014, Critical reviews in oncogenesis.

[13]  F. Melis,et al.  Natural killer cells responsiveness to physical exercise: A brief review , 2013 .

[14]  S. Maddika,et al.  WD Repeat Protein WDR48 in Complex with Deubiquitinase USP12 Suppresses Akt-dependent Cell Survival Signaling by Stabilizing PH Domain Leucine-rich Repeat Protein Phosphatase 1 (PHLPP1)* , 2013, The Journal of Biological Chemistry.

[15]  D. Cooper,et al.  Impact of brief exercise on peripheral blood NK cell gene and microRNA expression in young adults. , 2013, Journal of applied physiology.

[16]  N. Habermann,et al.  Progressive resistance versus relaxation training for breast cancer patients during adjuvant chemotherapy: design and rationale of a randomized controlled trial (BEATE study). , 2013, Contemporary clinical trials.

[17]  N. Habermann,et al.  Randomized controlled trial to evaluate the effects of progressive resistance training compared to progressive muscle relaxation in breast cancer patients undergoing adjuvant radiotherapy: the BEST study , 2013, BMC Cancer.

[18]  H. Pircher,et al.  NK-cells have an impaired response to acute exercise and a lower expression of the inhibitory receptors KLRG1 and CD158a in humans with latent cytomegalovirus infection , 2012, Brain, Behavior, and Immunity.

[19]  Wei Shi,et al.  Optimizing the noise versus bias trade-off for Illumina whole genome expression BeadChips , 2010, Nucleic acids research.

[20]  B. Timmons,et al.  Human natural killer cell subsets and acute exercise: a brief review. , 2008, Exercise immunology review.

[21]  G. Lancaster Chapter 10 – Exercise and cytokines , 2006 .

[22]  C. Klebanoff,et al.  Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. , 2005, Trends in immunology.

[23]  D. Nieman Exercise Immunology: Practical Applications , 1997, International journal of sports medicine.

[24]  A. Cripps,et al.  The effect on immunity of long‐term intensive training in elite swimmers , 1995, Clinical and experimental immunology.

[25]  P. Freedson,et al.  Exercise and cancer: linkages with obesity? , 1996, Critical reviews in food science and nutrition.

[26]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[27]  D. Keast,et al.  Exercise and the Immune Response , 1988, Sports medicine.