Effects of exercise training on breast cancer metastasis in a rat model
Antonieta Alvarado
Área de Patología, Decanato de Ciencias Veterinarias, Universidad Centroccidental ‘Lisandro Alvarado’ (UCLA), Lara, Venezuela
Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, Vila Real, Portugal
Search for more papers by this authorRui M. Gil da Costa
Grupo de Oncologia Molecular e Patologia Viral, CI-IPOP, Instituto Português de Oncologia do Porto, Porto, Portugal
Faculdade de Engenharia, LEPABE, Universidade do Porto (FEUP), Porto, Portugal
Search for more papers by this authorAna I. Faustino-Rocha
Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, Vila Real, Portugal
Organic Chemistry of Natural Products and Foodstuffs (QOPNA), Department of Chemistry, Mass Spectrometry Center, University of Aveiro, Aveiro, Portugal
Search for more papers by this authorRita Ferreira
Organic Chemistry of Natural Products and Foodstuffs (QOPNA), Department of Chemistry, Mass Spectrometry Center, University of Aveiro, Aveiro, Portugal
Search for more papers by this authorCarlos Lopes
Grupo de Oncologia Molecular e Patologia Viral, CI-IPOP, Instituto Português de Oncologia do Porto, Porto, Portugal
Search for more papers by this authorCorresponding Author
Paula A. Oliveira
Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, Vila Real, Portugal
Correspondence:
Paula A. Oliveira
Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences University of Trás-os-Montes and Alto Douro
UTAD 5001-911
Vila Real
Portugal
Tel.: 351 25935000
Fax: 351 259350480
E-mail: [email protected]
Search for more papers by this authorBruno Colaço
Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, Vila Real, Portugal
Department of Zootechnics, School of Agrarian and Veterinary Sciences, UTAD, Vila Real, Portugal
Search for more papers by this authorAntonieta Alvarado
Área de Patología, Decanato de Ciencias Veterinarias, Universidad Centroccidental ‘Lisandro Alvarado’ (UCLA), Lara, Venezuela
Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, Vila Real, Portugal
Search for more papers by this authorRui M. Gil da Costa
Grupo de Oncologia Molecular e Patologia Viral, CI-IPOP, Instituto Português de Oncologia do Porto, Porto, Portugal
Faculdade de Engenharia, LEPABE, Universidade do Porto (FEUP), Porto, Portugal
Search for more papers by this authorAna I. Faustino-Rocha
Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, Vila Real, Portugal
Organic Chemistry of Natural Products and Foodstuffs (QOPNA), Department of Chemistry, Mass Spectrometry Center, University of Aveiro, Aveiro, Portugal
Search for more papers by this authorRita Ferreira
Organic Chemistry of Natural Products and Foodstuffs (QOPNA), Department of Chemistry, Mass Spectrometry Center, University of Aveiro, Aveiro, Portugal
Search for more papers by this authorCarlos Lopes
Grupo de Oncologia Molecular e Patologia Viral, CI-IPOP, Instituto Português de Oncologia do Porto, Porto, Portugal
Search for more papers by this authorCorresponding Author
Paula A. Oliveira
Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, Vila Real, Portugal
Correspondence:
Paula A. Oliveira
Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences University of Trás-os-Montes and Alto Douro
UTAD 5001-911
Vila Real
Portugal
Tel.: 351 25935000
Fax: 351 259350480
E-mail: [email protected]
Search for more papers by this authorBruno Colaço
Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, Vila Real, Portugal
Department of Zootechnics, School of Agrarian and Veterinary Sciences, UTAD, Vila Real, Portugal
Search for more papers by this authorSummary
Exercise training is thought to play a protective role against cancer development and metastasis, either by reducing hormonal stimulation of hormone-dependent cancers or by reducing the permeability of vascular walls towards invading metastatic cells. The purpose of this work was to evaluate the role of long-term exercise training in the development and metastasis of breast cancer, in an immune-competent 1-methyl-1-nitrosourea (MNU) induced rat model. A single MNU dose was administered to Sprague-Dawley rats at 50 days of age and the rats were subjected to exercise training on a treadmill at 20 m/min, 60 min/day, 5 days/week for 35 weeks. Exercised animals developed slightly less (2.30 ± 1.42) tumours per animal than sedentary animals (2.55 ± 1.44) and did not develop any metastasis, while two pulmonary metastases were observed in the sedentary group. All primary neoplasms and their metastases were positive for oestrogen (ER) α and progesterone (PR) receptors, indicating high hormonal sensitivity. Interestingly, exercise training increased circulating oestrogen levels, thus suggesting that the mechanism might involve either or both of a protective hormone-independent effect and modulation of tumoural vascularization.
References
- Alvarado A., Faustino-Rocha A.I., Ferreira R. et al. (2016) Prognostic Factors in an Exercised Model of Chemically-induced Mammary Cancer. Anticancer Res. 36, 2181–2188.
- Aoi W., Naito Y., Takagi T. et al. (2010) Regular exercise reduces colon tumorigenesis associated with suppression of iNOS. Biochem. Bioph. Res. Co. 399, 14–19.
- Bae S.Y., Kim S., Lee J.H. et al. (2015) Poor prognosis of single hormone receptor-positive breast cancer: similar outcome as triple-negative breast cancer. BMC Cancer 15, 1–9.
- Cummings M.C., Simpson P.T., Reid L.E. et al. (2014) Metastatic progression of breast cancer: insights from 50 years of autopsies. J. Pathol. 232, 23–31.
- Faustino-Rocha A., Oliveira P.A., Pinho-Oliveira J. et al. (2013a) Estimation of rat mammary tumor volume using caliper and ultrasonography measurements. Lab. Anim. (NY) 42, 217–224.
- Faustino-Rocha A.I., Silva A., Gabriel J. et al. (2013b) Ultrasonographic, thermographic and histologic evaluation of MNU-induced mammary tumors in female Sprague-Dawley rats. Biomed. Pharmacother. 67, 771–776.
- Faustino-Rocha A.I., Ferreira R., Oliveira P.A., Gama A. & Ginja M. (2015) N-Methyl-N-nitrosourea as a mammary carcinogenic agent. Tumor Biol. 36, 9095–9117.
- Faustino-Rocha A.I., Gama A., Oliveira P.A. et al. (2016a) Ultrasonography as the gold standard for in vivo volumetric determination of chemically-induced mammary tumors. In Vivo 30, 465–472.
- Faustino-Rocha A.I., Gama A., Oliveira P.A. et al. (2016b) Effects of lifelong exercise training on mammary tumorigenesis induced by MNU in female Sprague-Dawley rats. Clin.Exp.Med. Epub ahead of print. doi: 10.1007/s10238-016-0419-0.
10.1007/s10238‐016‐0419‐0 Google Scholar
- Faustino-Rocha A.I., Silva A., Gabriel J. et al. (2016c) Long-term exercise training as a modulator of mammary cancer vascularization. Biomed. Pharmacother. 81, 273–280.
- Forbes D., Blom H., Kostomitsopoulos N., Moore G. & Perretta G. (2007) Felasa Euroguide on the Accommodation and Care of Animals Used for Experimental and Other Scientific Purposes. London: Royal Society of Medicine.
- Gago-Dominguez M., Jiang X.J. & Castelao J.E. (2007) Lipid peroxidation and the protective effect of physical exercise on breast cancer. Med. Hypotheses 68, 1138–1143.
- Grewal J., Zhou H.D., Factor R. & Kesari S. (2010) Isolated loss of hormonal receptors in leptomeningeal metastasis from estrogen receptor-and progesterone receptor-positive lobular breast cancer. J. Clin. Oncol. 28, E200–E202.
- Kariagina A., Xie J.W., Langohr I.M., Opreanu R.C., Basson M.D. & Haslam S.Z. (2013) Progesterone stimulates proliferation and promotes cytoplasmic localization of the cell cycle inhibitor p27 in steroid receptor positive breast cancers. Horm. Cancer 4, 381–390.
- Kayser K., Biechele U., Kayser G. et al. (1998) Pulmonary metastases of breast carcinomas: ligandohistochemical, nuclear, and structural analysis of primary and metastatic tumors with emphasis on period of occurrence of metastases and survival. J. Surg. Oncol. 69, 137–146.
10.1002/(SICI)1096-9098(199811)69:3<137::AID-JSO4>3.0.CO;2-L CAS PubMed Web of Science® Google Scholar
- Lanari C., Lamb C.A., Fabris V.T. et al. (2009) The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer. Endocr. Relat. Cancer 16, 333–350.
- Malicka I., Siewierska K., Pula B. et al. (2015) The effect of physical training on the N-methyl-N-nitrosourea-induced mammary carcinogenesis of Sprague-Dawley rats. Exp. Biol. Med. 240, 1408–1415.
- McCormick D.L., Adamowski C.B., Fiks A. & Moon R.C. (1981) Lifetime dose-response relationships for mammary-tumor induction by a single administration of N-Methyl-N-Nitrosourea. Cancer Res. 41, 1690–1694.
- McCullough D.J., Stabley J.N., Siemann D.W. & Behnke B.J. (2014) Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise. J. Natl Cancer Inst. 106, 1–8.
- McGuire W. & Clark G. (1986) Role of progesterone receptors in breast cancer. CA Cancer J. Clin. 36, 302–309.
- McTiernan A., Tworoger S.S., Ulrich C.M. et al. (2004) Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial. Cancer Res. 64, 2923–2928.
- Mohammed H., Russell I.A., Stark R. et al. (2015) Progesterone receptor modulates ERalpha action in breast cancer. Nature 523, 313–317.
- Paceli R.B., Cal R.N., Dos Santos C.H.F. et al. (2012) The influence of physical activity in the progression of experimental lung cancer in mice. Pathol. Res. Pract. 208, 377–381.
- Padrão A.I., Moreira-Goncalves D., Oliveira P.A. et al. (2015) Endurance training prevents TWEAK but not myostatin-mediated cardiac remodelling in cancer cachexia. Arch. Biochem. Biophys. 567, 13–21.
- Perse M., Cerar A., Injac R. & Strukelj B. (2009) N-methylnitrosourea induced breast cancer in rat, the histopathology of the resulting tumours and its drawbacks as a model. Pathol. Oncol. Res. 15, 115–121.
- Russo J. & Russo I.H. (2000) Atlas and histologic classification of tumors of the rat mammary gland. J. Mammary Gland Biol. Neoplasia 5, 187–200.
- Soares-Maia R., Faustino-Rocha A., Teixeira-Guedes C. et al. (2013) MNU-induced rat mammary carcinomas: immunohistology and estrogen receptor expression. J. Environ. Pathol. Toxicol. Oncol. 32, 157–163.
- Tai S.Y., Hsieh H.M., Huang S.P. & Wu M.T. (2016) Hair dye use, regular exercise, and the risk and prognosis of prostate cancer: multicenter case-control and case-only studies. BMC Cancer 16, 1–12.
- Thompson H.J. (1994) Effect of exercise intensity and duration on the induction of mammary carcinogenesis. Cancer Res. 54, S1960–S1963.
- Thompson H.J., Wolfe P., McTiernan A., Jiang W.Q. & Zhu Z.J. (2010) Wheel running-induced changes in plasma biomarkers and carcinogenic response in the 1-Methyl-1-Nitrosourea-induced rat model for breast cancer. Cancer Prev. Res. 3, 1484–1492.
- Valastyan S. & Weinberg R.A. (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292.
- Vici P., Pizzuti L., Natoli C. et al. (2015) Triple positive breast cancer: a distinct subtype? Cancer Treat. Rev. 41, 69–76.
- Westerlind K.C. (2003) Physical activity and cancer prevention-mechanisms. Med. Sci. Sports Exerc. 35, 1834–1840.
- Whittal-Strange K.S., Chadau S. & Parkhouse W.S. (1998) Exercise during puberty and NMU induced mammary tumorigenesis in rats. Breast Cancer Res. Tr. 47, 1–8.
- Wolff G. & Toborek M. (2013) Targeting the therapeutic effects of exercise on redox-sensitive mechanisms in the vascular endothelium during tumor progression. IUBMB Life 65, 565–571.
- Wolff G., Balke J.E., Andras I.E., Park M. & Toborek M. (2014) Exercise modulates redox-sensitive small GTPase activity in the brain microvasculature in a model of brain metastasis formation. PLoS ONE 9, e97033.
- Wolff G., Davidson S.J., Wrobel J.K. & Toborek M. (2015) Exercise maintains blood-brain barrier integrity during early stages of brain metastasis formation. Biochem. Bioph. Res. Co. 463, 811–817.
- Wu S.G., Sun J.Y., Yang L.C. et al. (2016) Patterns of distant metastasis in Chinese women according to breast cancer subtypes. Oncotarget 7, 47975–47984.