The effects of interval aerobic training on mesenchymal biomarker gene expression, the rate of tumor volume, and cachexia in mice with breast cancer

Document Type : Original Article


1 Department of Exercise Physiology (Biochemistry and Metabolism), Faculty of Sports Sciences, Ferdowsi University of Mashhad, Mashhad, Iran

2 Department of Physiology, Faculty of Sports Sciences, Ferdowsi University of Mashhad, Mashhad, Iran

3 Department of Exercise Physiology, Faculty of Sports Sciences, Ferdowsi University of Mashhad, Mashhad, Iran

4 Department of Sports Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran


Objective(s): It seems that regular exercise can have inhibitory effects on the progression of breast cancer. This study, therefore, aimed to investigate the influences of interval aerobic training on mesenchymal biomarker gene expression, muscle cachexia, and tumor volume changes in mice with breast cancer.
Materials and Methods: Thirty-two female Balb/c mice were allocated to four groups: Exercise Tumor Exercise, Rest Tumor Rest (Control), Rest Tumor Exercise, and Exercise Tumor Rest. Interval aerobic training was done 6 weeks before and 4 weeks after tumor induction. Weight test and inverted screen test were carried out as muscle function tests. Data were analyzed using one-way ANOVA and HSD post hoc.
Results: The results showed a significant decrease in gene expressions of Twist, Vimentin, and TGF-β in Exercise Tumor Exercise group in comparison with the Control group (P<0.05). Remarkable reduction of the rate of tumor volume was also observed in two training groups (Rest Tumor Exercise, Exercise Tumor Exercise) compared with the control group. According to function tests’ results, muscle functions were diminished due to cancer, but interval aerobic training can keep muscles in a normally-functioning state in cancer (P<0.05).
Conclusion: Considering final results, a period of interval aerobic training can be used not only as a prevention method, but also help cancer treatment and impede cachexia by tumor volume reduction, decrease mesenchymal biomarker gene expression, and increase muscle strength functions.


1. Enayatrad M, Amoori N, Salehiniya H. Epidemiology and trends in breast cancer mortality in iran. Ir J Pub Health 2015; 44:430-431.
2. Motamedi M, Hashemzadeh Chaleshtori M, Ghasemi S, Kheiri S, Haji Gholami A. The association of mir-451 and mir-21 in plasma with lymph node metastases in breast cancer. J Babol Univ Med Sci 2018; 20:16-12.
3. Chai J, Modak C, Mouazzen W, Narvaez R, Pham J. Epithelial or mesenchymal: Where to draw the line? Biosci trends 2010;4:130-142.
4. Kalluri R, Neilson E. Epithelial-mesenchymal transition and its implications for fibrosis. JClin Invest 2003;112:1776-1784.
5. Kalcheim C. Epithelial–mesenchymal transitions during neural crest and somite development. J Clin Med 2015;5:716-725.
6. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2010; 120:1786.
7. Satelli A, Li S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci 2011;68:3033-3046.
8. Wu Y, Zhang X, Salmon M, Lin X, Zehner ZE. TGFbeta1 regulation of vimentin gene expression during differentiation of the C2C12 skeletal myogenic cell line requires Smads, AP-1 and Sp1 family members. Biochimica et Biophysica Acta (BBA) 2007;1773:427-439.
9. Clark D, Coker R. Transforming growth factor-beta (TGF-β). Int J Biochem Cell Biol 1998; 30: 293-298.
10. Hwangbo C, Tae N, Lee S, Kim O, Park O, Kim J. Syntenin regulates TGF-β1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-β type I receptor internalization. Oncogene 2016;35:83-89.
11. Derynk R, Zhang Y, Feng XH. Smads: Transcriptional activators of TGF- beta responses. Cell 1998; 95: 737-740.
12. Imamura T, Hikita A, Inoue Y. The roles of TGF-β signaling in carcinogenesis and breast cancer metastasis. Breast Cancer 2012; 19:118-124.
13. Bierie B, Moses HL, Transforming growth factor beta (TGF-β) and inflammation in cancer, Cytokine and Growth Factor Reviews 2010; 21: 49-59.
14. Scheel C, Weinberg RA, editors. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin cancer biol 2012;22:396-403.
15. Fearon K, Strasser F, Anker S, Bosaeus I, Bruera E, Fainsinger R. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011; 12:489-495.
16. Thomas DR. Loss of skeletal muscle mass in aging: examining the relationship of starvation, sarcopenia and cachexia. Clin Nutr 2007; 26: 389-399.
17. Moley JF, Aamodt R, Rumble W, Kaye W, Norton JA. Body cell mass in cancer bearing and anorexia patients. J Parenter Enteral Nutr 1987; 11: 219-222.
18. Parajuli P, Kumar S, Loumaye A, Singh P, Eragamreddy S, Nguyen TL. Twist1 activation in muscle progenitor cells causes muscle loss akin to cancer cachexia. Dev Cell 2018; 45: 712-725.
19. Lira FS, Neto JC, Seelaender M. Exercise training as treatment in cancer cachexia. Appl Physiol Nutr Metab 2014; 39:679-686.
20. Powers SK, Ji LL, Leeuwenburgh C. Exercise training-induced alterations in skeletal muscle antioxidant capacity: a brief review. Med Sci Sports Exerc 1999; 31: 987-997.
21. Zhang L, Liu W, Gao Y, Qin Y, Wu R. The expression of IL-6 and STAT3 might predict progression and unfavorable prognosis in Wilms’ tumor. Biochem Biophys Res Commun 2013; 435:408-413.
22. Meyer K, Samek L, Schwaibold M, Westbrook S, Hajric R, Lehmann M. Physical responses to different modes of interval exercise in patients with chronic heart failure: Application to exercise training. Eur Heart J 1996; 17:1040-1047.
23. Ranjbar K, Agha Alinejad H, Shahbazi SH, Molanouri Shamsi SH. Interval aerobic exercise and selenium nanoparticle stimulate autophagy in mice with cancer cachexia. Int J Cancer Oncol 2018;5:35-40.
24. Baliga MS, Meleth S, Katiyar SK. Growth inhibitory and antimetastatic effect of green tea polyphenols on metastasis-specific mouse mammary carcinoma 4T1cells invitro and invivo systems. Clin Cancer Res 2005;11:1918-1927.
25. Jones L, Viglianti B, Tashjian J, Kothadia S, Keir S, Freedland S. Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer. J Appl Physiol 2009;108:343-348.
26. Deacon RM. Measuring the Strength of Mice. J Vis Exp 2013; 76: 2610.
27. Drabsch Y, Ten Dijke P. TGF-β signaling in breast cancer cell invasion and bone metastasis. J mammary gland biol neoplasia 2011;16:97-108.
28. Lee J, Roh K-B, Kim S-C, Lee J, Park D. Soy peptide-induced stem cell proliferation: involvement of ERK and TGF-β1. J Nutr Biochem 2012;23:1341-1351.
29. Mulder KM. Role of Ras and Mapks in TGFβ signaling Cytokine Growth Factor Rev 2000; 11:23-35.
30. Medeiros A, Oliveira E, Gianolla R, Casarini D, Negrão C, Brum P. Swimming training increases cardiac vagal activity and induces cardiac hypertrophy in rats. Braz J Med Biol Res 2004; 37:1909-1917.
31. Hunter C, Jones S. IL-6 as a keystone cytokine in health and disease. Nat Immunol 2015; 16: 448-457.
32. Abdalla DR, Murta EF, Michelin MA. The influence of physical activity on the profile of immune response cells and cytokine synthesis in mice with experimental breast tumors induced by 7, 12-dimethylbenzanthracene. Eur J Cancer Prev 2013; 22: 251-258.
33. Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L, Pedersen BK. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab 2011;301: 504-510.
34. Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW, Mackey JR. Randomized controlled trial of exercise and blood immune function in postmenopausal breast cancer survivors. J Appl Physiol 2005;98:1534-1540.
35. Goh J, Tsai J, Bammler TK. Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dose-dependent manner. PLOS ONE 2013; 11: 80123.
36. Colbert LH, Westerlind KC, Perkins SN, Haines DC, Berrigan D, Donehower LA. Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer. Med Sci Sport Exer 2009;41:1597.
37. Donatto FF, Neves RX, Rosa FD, Camargo RG, Ribeiro H, Matos-Neto EM.  Resistance exercise modulates lipid plasma profile and cytokine content in the adipose tissue of tumour-bearing rats. Cytokine 2013;61:426-432.
38. Lira FS, Yamashita AS, Rosa JC, Tavares FL, Caperuto E, Carnevali LC.  Hypothalamic inflammation is reversed by endurance training in anorectic-cachectic rats. Nutr Metab 2011; 8: 60.
39. Parajuli P, Kumar S, Loumaye A, Singh P, Eragamreddy S, Nguyen TL. Twist1 activation in muscle progenitor cells causes muscle loss akin to cancer cachexia. Dev Cell 2018;45:712-725.
40. Blum D, Omlin A, Baracos VE, Solheim TS, Tan BH, Stone P. Cancer cachexia: a systematic literature review of items and domains associated with involuntary weight loss in cancer. Crit Rev Oncol Hemat 2011;80:114-144.
41. Vaughan, P. Martin, and P. A. Lewandowski. Cancer cacheia: impact, mechanisms and emerging treatments. J Cachexia Sarcopeni 2013;4: 95-109.