Mammalian Genome

, Volume 19, Issue 3, pp 179–189

Genotype × diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis

  • Ryan R. Gordon
  • Kent W. Hunter
  • Michele La Merrill
  • Peter Sørensen
  • David W. Threadgill
  • Daniel Pomp
Article

Abstract

High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F2 mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F2 mice either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL × diet interaction effects. Here we describe effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer latency but increased tumor growth and pulmonary metastases occurrence over an equivalent time. We identified 25 modifier loci for mammary cancer and pulmonary metastasis, likely representing 13 unique loci after accounting for pleiotropy, and novel QTL × diet interactions at a majority of these loci. These findings highlight the importance of accurately modeling not only the human cancer characteristics in mice but also the environmental exposures of human populations.

References

  1. Allan MF, Eisen EJ, Pomp D (2005) Genomic mapping of direct and correlated responses to long-term selection for rapid growth rate in mice. Genetics 170:1863–1877PubMedCrossRefGoogle Scholar
  2. American Cancer Society (2007) Breast Cancer Overview. Available at http://www.cancer.org/downloads/stt/CFF2007EstCsDths07.pdf. Accessed on 8 May 2007
  3. Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33 Suppl:238–244CrossRefGoogle Scholar
  4. Boyd DB (2003) Insulin and cancer. Integr Cancer Ther 2:315–329PubMedCrossRefGoogle Scholar
  5. Bray GA (2002) The underlying basis for obesity: relationship to cancer. J Nutr 132:3451S–3455SPubMedGoogle Scholar
  6. Cade JE, Burley VJ, Greenwood DC (2007) Dietary fibre and risk of breast cancer in the UK Women’s Cohort Study. Int J Epidemiol 36:431-438PubMedCrossRefGoogle Scholar
  7. Cho E, Spiegelman D, Hunter DJ, Chen WY, Stampfer MJ et al (2003) Premenopausal fat intake and risk of breast cancer. J Natl Cancer Inst 95:1079–1085PubMedGoogle Scholar
  8. Crawford NP, Ziogas A, Peel DJ, Hess J, Anton-Culver H et al (2006) Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer. Breast Cancer Res 8:R16PubMedCrossRefGoogle Scholar
  9. Gordon RR, Hunter KW, Sørensen P, Pomp D (2008) Genotype × diet interactions in mice predisposed to mammary cancer: I. Body weight and fat. Mamm Genome 19:000-000Google Scholar
  10. Guy CT, Cardiff RD, Muller WJ (1992) Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12:954–961PubMedGoogle Scholar
  11. Houzelstein D, Bullock SL, Lynch DE, Grigorieva EF, Wilson VA et al (2002) Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4. Mol Cell Biol 22:3794–3802PubMedCrossRefGoogle Scholar
  12. Hunter KW, Broman KW, Voyer TL, Lukes L, Cozma D et al (2001) Predisposition to efficient mammary tumor metastatic progression is linked to the breast cancer metastasis suppressor gene Brms1. Cancer Res 61:8866–8872PubMedGoogle Scholar
  13. Hursting SD, Lashinger LM, Colbert LH, Rogers CJ, Wheatley KW et al (2007) Energy balance and carcinogenesis: underlying pathways and targets for intervention. Curr Cancer Drug Targets 7:484–491PubMedCrossRefGoogle Scholar
  14. Kaklamani VG, Linos A, Kaklamani E, Markaki I, Koumantaki Y et al (1999) Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults. J Clin Oncol 17:3291–3298PubMedGoogle Scholar
  15. Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF et al (2003) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95:1218–1226PubMedCrossRefGoogle Scholar
  16. Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA et al (2004) Diet, nutrition and the prevention of cancer. Public Health Nutr 7:187–200PubMedCrossRefGoogle Scholar
  17. Kim EH, Willett WC, Colditz GA, Hankinson SE, Stampfer MJ et al (2006) Dietary fat and risk of postmenopausal breast cancer in a 20-year follow-up. Am J Epidemiol 164:990–997PubMedCrossRefGoogle Scholar
  18. King MC, Marks JH, Mandell JB, New York Breast Cancer Study Group (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643–646PubMedCrossRefGoogle Scholar
  19. Lancaster M, Rouse J, Hunter KW (2005) Modifiers of mammary tumor progression and metastasis on mouse chromosomes 7, 9, and 17. Mamm Genome 16:120–126PubMedCrossRefGoogle Scholar
  20. Le Voyer T, Lu Z, Babb J, Lifsted T, Williams M et al (2000) An epistatic interaction controls the latency of a transgene-induced mammary tumor. Mamm Genome 11:883–889PubMedCrossRefGoogle Scholar
  21. Lebreton CM, Visscher PM, Haley CS, Semikhodskii A, Quarrie SA (1998) A nonparametric bootstrap method for testing close linkage vs. pleiotropy of coincident quantitative trait loci. Genetics 150:931–942PubMedGoogle Scholar
  22. Lee MM, Chang IY, Horng CF, Chang JS, Cheng SH et al (2005) Breast cancer and dietary factors in Taiwanese women. Cancer Causes Control 16:929–937PubMedCrossRefGoogle Scholar
  23. National Cancer Institute (2005) What you need to know about breast cancer. Available at http://www.cancer.gov/cancertopics/wyntk/breast. Accessed on 8 May 2007
  24. Park YG, Zhao X, Lesueur F, Lowy DR, Lancaster M et al (2005) Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nat Genet 37:1055–1062PubMedCrossRefGoogle Scholar
  25. Rohan TE, Li SQ, Hartwick R, Kandel RA (2006) p53 Alterations and protein accumulation in benign breast tissue and breast cancer risk: a cohort study. Cancer Epidemiol Biomarkers Prev 15:1316–1323PubMedCrossRefGoogle Scholar
  26. Rose DP, Connolly JM, Meschter CL (1991) Effect of dietary fat on human breast cancer growth and lung metastasis in nude mice. J Natl Cancer Inst 83:1491–1495PubMedCrossRefGoogle Scholar
  27. Salazar-Martinez E, Lazcano-Ponce E, Sanchez-Zamorano LM, Gonzalez-Lira G, Escudero-de los Rios P et al (2005) Dietary factors and endometrial cancer risk. Results of a case-control study in Mexico. Int J Gynecol Cancer 15:938–945PubMedCrossRefGoogle Scholar
  28. Smith-Warner SA, Spiegelman D, Adami HO, Beeson WL, van den Brandt PA et al (2001) Types of dietary fat and breast cancer: a pooled analysis of cohort studies. Int J Cancer 92:767–774PubMedCrossRefGoogle Scholar
  29. SAS (2002) Release 9.1 TS level 1M3. Cary, NC: SAS InstituteGoogle Scholar
  30. Schaffler A, Scholmerich J, Buechler C (2007) Mechanisms of disease: adipokines and breast cancer - endocrine and paracrine mechanisms that connect adiposity and breast cancer. Nat Clin Pract Endocrinol Metab 3:345–354PubMedCrossRefGoogle Scholar
  31. Seaton G, Haley CS, Knott SA, Kearsey M, Visscher PM (2002) QTL Express: mapping quantitative trait loci in simple and complex pedigrees. Bioinformatics 18:339–340PubMedCrossRefGoogle Scholar
  32. Senzaki H, Iwamoto S, Ogura E, Kiyozuka Y, Arita S et al (1998) Dietary effects of fatty acids on growth and metastasis of KPL-1 human breast cancer cells in vivo and in vitro. Anticancer Res 18:1621–1627PubMedGoogle Scholar
  33. Shi R, Yu H, McLarty J, Glass J (2004) IGF-1 and breast cancer: a meta-analysis. Int J Cancer 111:418–423PubMedCrossRefGoogle Scholar
  34. Song CG, Hu Z, Wu J, Luo JM, Shen ZZ et al (2006) The prevalence of BRCA1 and BRCA2 mutations in eastern Chinese women with breast cancer. J Cancer Res Clin Oncol 132:617–626PubMedCrossRefGoogle Scholar
  35. Sporn MB (1996) The war on cancer. Lancet 347:1377–1381PubMedCrossRefGoogle Scholar
  36. Stoll BA (1998) Western diet, early puberty, and breast cancer risk. Breast Cancer Res Treat 49:187–193PubMedCrossRefGoogle Scholar
  37. Terry MB, Zhang FF, Kabat G, Britton JA, Teitelbaum SL et al (2006) Lifetime alcohol intake and breast cancer risk. Ann Epidemiol 16:230–240PubMedCrossRefGoogle Scholar
  38. Wakai K, Tamakoshi K, Date C, Fukui M, Suzuki S et al (2005) Dietary intakes of fat and fatty acids and risk of breast cancer: a prospective study in Japan. Cancer Sci 96:590–599PubMedCrossRefGoogle Scholar
  39. Walsh T, Casadei S, Coats KH, Swisher E, Stray SM et al (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379–1388PubMedCrossRefGoogle Scholar
  40. World Health Organization (2006) Cancer. Available at http://www.who.int/mediacentre/factsheets/fs297/en/index.html. Accessed on 8 May 2007

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ryan R. Gordon
    • 1
  • Kent W. Hunter
    • 2
  • Michele La Merrill
    • 3
  • Peter Sørensen
    • 4
  • David W. Threadgill
    • 3
    • 5
  • Daniel Pomp
    • 1
    • 5
    • 6
  1. 1.Department of NutritionUniversity of North CarolinaChapel HillUSA
  2. 2.Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaUSA
  3. 3.Department of GeneticsUniversity of North CarolinaChapel HillUSA
  4. 4.Faculty of Agricultural SciencesAarhus UniversityAarhusDenmark
  5. 5.Center for Environmental Health and Susceptibility, Clinical Nutrition Research Unit, Lineberger Cancer Center, and Carolina Genome Sciences CenterUniversity of North CarolinaChapel HillUSA
  6. 6.Department of Cell and Molecular PhysiologyUniversity of North CarolinaChapel HillUSA

Personalised recommendations