Share This Article:

The Anti-Tumor Effect of a High Caloric Diet in the PyMT Mouse Breast Cancer Model Is Initiated by an Increase in Metabolic Rate

Abstract Full-Text HTML Download Download as PDF (Size:2326KB) PP. 718-730
DOI: 10.4236/jct.2012.325091    6,276 Downloads   8,547 Views   Citations

ABSTRACT

Obesity is associated with an increased risk of mortality from certain types of cancer, including cancer of the breast. Because obesity is associated with multiple risk factors, however, the exact reasons remain unclear. The objective of this study was to determine which of the risk factors associated with obesity are related to enhanced tumor development. The MMTV-PyMT mouse model develops mammary tumors which share numerous characteristics with those of humans. We challenged these mice with a high fat/high carbohydrate, high caloric (HC) diet, and looked for relationships between enhanced primary tumor development and adiposity, various aspects of glucose homeostasis, and metabolic factors. The HC diet enhanced tumor progression in PyMT mice. While mice on the HC diet also developed increased adiposity, hyperglycemia and hyperinsulinemia, none of these risk factors was found to be associated with the observed increases in tumor growth. Rather, we found that while overall, tumor growth was enhanced in HC diet-fed mice compared to those maintained on a regular diet, it was attenuated in individuals by an HC diet-induced increase in metabolic rate and decrease in respiratory exchange ratio. Tumor size in HC diet-fed mice was directly related to p38 phosphorylation and Bcl-2 inhibition, and the degree of vascularization of these tumors was closely and indirectly related to the rate of mouse oxygen consumption. The data suggest that an increase in metabolic rate and oxygen consumption, induced by the introduction of a high caloric diet, has a protective effect against tumor growth by increasing the activity levels of the tumor suppressor p38 and decreasing the activity of the antiapoptoic protein Bcl-2, as well as by reducing hypoxia-induced tumor vascularization.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

L. C. Enns and W. C. Ladiges, "The Anti-Tumor Effect of a High Caloric Diet in the PyMT Mouse Breast Cancer Model Is Initiated by an Increase in Metabolic Rate," Journal of Cancer Therapy, Vol. 3 No. 5A, 2012, pp. 718-730. doi: 10.4236/jct.2012.325091.

References

[1] R. Samper-Ternent and S. Al Snih, “Obesity in Older Adults: Epidemiology and Implications for Disability and Disease,” Reviews in Clinical Gerontology, Vol. 22, No. 1, 2012, pp. 10-34.
[2] J. R. Jaggers, X. Sui, S. P. Hooker, M. J, LaMonte, C. E. Matthews, G. A. Hand and S. N. Blair, “Metabolic Syndrome and Risk of Cancer Mortality in Men,” European Journal of Cancer, Vol. 45, No. 10, 2009, pp. 1831-1838.
[3] P. Pothiwala, S. K. Jain and S. Yaturu, “Metabolic Syndrome and Cancer,” Metabolic Syndrome and Related Disorders, Vol. 7, No. 4, 2009, pp. 279-288.
[4] World Cancer Research Fund/American Institute for Cancer Research, “Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective,” Washington DC, 2007.
[5] G. Taubes, “Unraveling the Obesity-Cancer Connection,” Science, Vol. 335, No. 6066, 2012, pp. 28-32.
[6] J. M. Petrelli, E. E. Calle, C. Rodriguez and M. J. Thun, “Body Mass Index, Height, and Postmenopausal Breast Cancer Mortality in a Prospective Cohort of US Women,” Cancer Causes and Control, Vol. 13, No. 4, 2002, pp. 325-332.
[7] C. T. Guy, R. D. Cardiff and W. J. Muller, “Induction of Mammary Tumors by Expression of Polyomavirus Middle T Oncogene: A Transgenic Mouse Model for Metastatic Disease,” Molecular and Cellular Biology, Vol. 12, No. 3, 1992, pp. 965-961.
[8] L. C. Enns, J. F. Morton, R. S. Mangalindan, G. S. McKnight, M. W. Schwartz, M. R. Kaeberlein, B. K. Kennedy, P. S. Rabinovitch and W. C. Ladiges, “Attenuation of Age-Related Metabolic Dysfunction in Mice with a Targeted Disruption of the Cbeta Subunit of Protein Kinase A,” The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 64, No. 12, 2009, pp. 1221-1231.
[9] E. Y. Lin, J. G. Jones, P. Li, L. Zhu, K. D. Whitney, W. J. Muller and J. W. Pollard, “Progression to Malignancy in the Polyoma Middle T Oncoprotein Mouse Breast Cancer Model Provides a Reliable Model for Human Diseases,” American Journal of Pathology, Vol. 163, No. 5, pp. 2113-2126.
[10] P. M. Treuting, L. I. Chen, B. S. Buetow, W. Zeng, T. A. Birkebak, V. L. Seewaldt, K. M. Sommer, M. Emond M, L. Maggio-Price and K. Swisshelm, “Retinoic Acid Receptor Beta2 Inhibition of Metastasis in Mouse Mammary Gland Xenografts,” Breast Cancer Research and Treatment, Vol. 72, No. 1, 2002, pp. 79-88.
[11] J. Goh, L. Enns, S. Fatemie, H. Hopkins, J. Morton, C. Pettan-Brewer and W. Ladiges, “Mitochondrial Targeted Catalase Suppresses Invasive Breast Cancer in Mice,” BMC Cancer, Vol. 11, 2011, p. 191. doi: 10. 1186/1471-2407-11-191.
[12] G. Llaverias, C. Danilo, I. Mercier, K. Daumer, F. Capozza, T. M. Williams, F. Sotgia, M. P. Lisanti and P. G. Frank, “Role of Cholesterol in the Development and Progression of Breast Cancer,” American Journal of Pathology, Vol. 178, No. 1, 2011, pp. 402-412.
[13] F. Xue and K. B. Michels, “Diabetes, Metabolic Syndrome, and Breast Cancer: A Review of the Current Evidence,” American Journal of Clinical Nutrition, Vol. 86, No. 3, 2007, pp. s823-s835.
[14] A. S. Glicksman and R. W. Rawson, “Diabetes and Altered Carbohydrate Metabolism in Patients with Cancer,” Cancer, Vol. 9, No. 6, 1956, pp. 1127-1134.
[15] O. Warburg, “On the Origin of Cancer Cells,” Science, Vol. 123, No. 3191, 1956, pp. 309-314.
[16] P. J. Goodwin, M. Ennis, K. I. Pritchard, M. E. Trudeau, J. Koo, Y. Madarnas, W. Hartwick, B. Hoffman and N. Hood, “Fasting Insulin and Outcome in Early-Stage Breast Cancer: Results of a Prospective Cohort Study,” Journal of Clinical Oncology, Vol. 20, No. 1, 2002, pp. 42-51.
[17] M. Ristow, “Oxidative Metabolism in Cancer Growth,” Current Opinions in Clinical Nutrition and Metabolic Care, Vol. 9, No. 4, 2006, pp. 339-345.
[18] R. A. Gatenby and R. J. Gillies, “Why Do Cancers Have High Aerobic Glycolysis?” Nature Reviews Cancer, Vol. 4, No. 11, 2004, pp. 891-899.
[19] D. G. Hardie, “AMP-Activated/SNF1 Protein Kinases: Conserved Guardians of Cellular Energy,” Nature Reviews Molecular Cell Biology, Vol. 8, No. 10, 2007, pp. 774-785.
[20] K. Inoki K, J. Kim and K.-L. Guan, “AMPK and mTOR in Cellular Energy Homeostasis and Drug Targets,” Annual Review of Pharmacology and Toxicology, Vol. 52, 2011, pp. 381-400.
[21] M. Schmidt, M. Kapp, M. Krockenberger, J. Dietl and U. Kammerer, “Glycolytic Phenotype in Breast Cancer: Activation of Akt, Up-Regulation of GLUT1, TKTL1 and Down-Regulation of M2PK,” Journal of Cancer Research and Clinical Oncology, Vol. 136, No. 2, 2010, pp. 219-25.
[22] M. K. Sung, J. Y. Yeon, S. Y. Park, J. H. Park and M. S. Choi, “Obesity-Induced Metabolic Stresses in Breast and Colon Cancer,” Annals of the New York Academy of Sciences, Vol. 1229, 2011, pp. 61-68. doi: 10. 1111/j. 1749-6632. 2011. 06094. x.
[23] K. B. Michels, K. L. Terry, W. C. Willett, “Longitudinal Study on the Role of Body Size in Premenopausal Breast Cancer,” Archives of Internal Medicine, Vol. 166, No. 21, 2006, pp. 2395-2402.
[24] B. M. Emerling, L. C. Platanias, E. Black, A. R. Nebreda, R. J. Davis and N. S. Chandel, “Mitochondrial Reactive Oxygen Species Activation of p38 Mitogen-Activated Protein Kinase Is Required for Hypoxia Signaling,” Molecular and Cellular Biology, Vol. 25, No. 12, 2005, pp. 4853-4862.
[25] Y. Ramiro-Cortes, A. Guemez-Gamboa and J. M. Andrade, “Reactive Oxygen Species Participate in the p38-Mediated Apoptosis Induced By Potassium Deprivation and Staurosporine in Cerebellar Granule Neurons,” The International Journal of Biochemistry and Cell Biology, Vol. 43, No. 9, 2011, pp. 1373-1382.
[26] J. Pan J, Q. Chang, X. Wang, Y. Son, Z. Zhang, G. Chen, J. Luo, Y. Bi, F. Chen, X. Shi, “Reactive Oxygen Species-Activated Akt/ASK1/p38 Signaling Pathway in Nickel Compound-Induced Apoptosis in BEAS 2B Cells,” Chemical Research in Toxicology, Vol. 23, No. 3, 2010, pp. 568-577.
[27] M. Pearl-Yafe, D. Halperin, O. Scheuerman and I. Fabian, “The p38 Pathway Partially Mediates Caspase-3 Activation Induced by Reactive Oxygen Species in Fanconi Anemia C cells,” Biochemical Pharmacology Vol. 67, No. 3, 2004, pp. 539-546.
[28] A. Van Laethem, K. Nys, S. Van Kelst, S. Claerhout, H. Ichijo, J. Vandenheede, M. Garmyn and P. Agostinis, “Apoptosis Signal Regulating Kinase-1 Connects Reactive Oxygen Species to p38 MAPK-Induced Mitochondrial Apoptosis in UVB-Irradiated Human Keratinocytes,” Free Radical Biology and Medicine, Vol. 41, No. 9, 2006, pp. 1361-71.
[29] W-S. Choi, D-S. Eom, B. S. Han, W. K. Kim, B. H. Han, E. J. Choi, T. H. Oh, G. J. Markelonis, J. W. Cho and Y. J. Oh, “Phosphorylation of p38 MAPK Induced by Oxidative Stress Is Linked to Activation of Both Caspase-8- and -9-Mediated Apoptotic Pathways in Dopaminergic Neurons,” Journal of Biological Chemistry Vol. 279, No. 19, 2004, pp. 20451-20460.
[30] P. Carmeliet and R. K. Jain, “Angiogenesis in Cancer and Other Diseases,” Nature, Vol. 407, No. 6801, 2000, pp. 249-257.
[31] T. W. Secomb, R. Hsu, E. T. Ong, J. F. Gross and M. W. Dewhirst, “Analysis of the Effects of Oxygen Supply and Demand on Hypoxic Fraction in Tumors,” Acta Oncologica, Vol. 34, No. 3, 1995, pp. 313-316.
[32] G. L. Semenza, “Angiogenesis Ischemic and Neoplastic Disorders,” Annual Review of Medicine, Vol. 54, 2003, pp. 17-28.
[33] B. J. Moeller, Y. Cao, Z. Vujaskovic, C. Y. Li, Z. A. Haroon and M. W. Dewhirst, “The relationship between Hypoxia and Angiogenesis,” Seminars in Radiation Oncology, Vol. 14, No. 3, 2004, pp. 215-221.
[34] B. D. Kavanagh, T. W. Secomb, R. Hsu, P-S. Lin, J. Venitz and M. W. Dewhirst, “A theoretical Model of the Effects of Reduced Hemoglobin-Oxygen Affinity on Tumor Oxygenation,” International Journal of Radiation Oncology Biology Physics, Vol. 53, No. 1, 2002, pp. 172-179.
[35] L. L. Spriet, C. G. Perry and J. L. Talanian, “Legal Pre-Event Nutritional Supplements to Assist Energy Metabolism,” Essays in Biochemistry, Vol. 44, 2008, pp. 27-43.
[36] M. Yu, N. K. Stepto, A. V. Chibalin, L. G. D. Fryer, D. Carling, A. Krook, J. A. Hawley and J. R. Zierath, “Metabolic and Mitogenic Signal Transduction in Human Skeletal Muscle After Intense Cycling Exercise,” Journal of Physiology, Vol. 546, Pt. 2, 2003, pp. 327-335.
[37] A. M. Harris, M. D. Jensen and J. A. Levine, “Weekly Changes in Basal Metabolic Rate with Eight Weeks of Overfeeding,” Obesity, Vol. 14, No. 4, 2006, pp. 690-695.

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.