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Breast Cancer Research and Treatment

, Volume 123, Issue 2, pp 333–344 | Cite as

Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy

  • Kathryn N. Phoenix
  • Frank Vumbaca
  • Melissa M. Fox
  • Rebecca Evans
  • Kevin P. Claffey
Preclinical study

Abstract

Dietary energy restriction has been shown to repress both mammary tumorigenesis and aggressive mammary tumor growth in animal studies. Metformin, a caloric restriction mimetic, has a long history of safe use as an insulin sensitizer in diabetics and has been shown to reduce cancer incidence and cancer-related mortality in humans. To determine the potential impact of dietary energy availability and metformin therapy on aggressive breast tumor growth and metastasis, an orthotopic syngeneic model using triple negative 66cl4 tumor cells in Balb/c mice was employed. The effect of dietary restriction, a standard maintenance diet or a diet with high levels of free sugar, were tested for their effects on tumor growth and secondary metastases to the lung. Metformin therapy with the various diets indicated that metformin can be highly effective at suppressing systemic metabolic biomarkers such as IGF-1, insulin and glucose, especially in the high energy diet treated animals. Long-term metformin treatment demonstrated moderate yet significant effects on primary tumor growth, most significantly in conjunction with the high energy diet. When compared to the control diet, the high energy diet promoted tumor growth, expression of the inflammatory adipokines leptin and resistin, induced lung priming by bone marrow-derived myeloid cells and promoted metastatic potential. Metformin had no effect on adipokine expression or the development of lung metastases with the standard or the high energy diet. These data indicate that metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events.

Keywords

Breast cancer Dietary energy restriction Metformin Metastasis Leptin Resistin 

Notes

Acknowledgments

The authors would like to thank Nancy Ryan and Xiaoxiao Hong for their technical assistance. This work was supported by NIH:NCI CA064436 and the Connecticut Breast Health Initiative, Inc.

Supplementary material

10549_2009_647_MOESM1_ESM.pdf (63 kb)
(PDF 63 kb)

References

  1. 1.
    Dal Maso L, Zucchetto A, Talamini R, Serraino D, Stocco CF, Vercelli M, Falcini F, Franceschi S (2008) Effect of obesity and other lifestyle factors on mortality in women with breast cancer. Int J Cancer 123(9):2188–2194CrossRefPubMedGoogle Scholar
  2. 2.
    Montazeri A, Sadighi J, Farzadi F, Maftoon F, Vahdaninia M, Ansari M, Sajadian A, Ebrahimi M, Haghighat S, Harirchi I (2008) Weight, height, body mass index and risk of breast cancer in postmenopausal women: a case-control study. BMC Cancer 8:278CrossRefPubMedGoogle Scholar
  3. 3.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348(17):1625–1638CrossRefPubMedGoogle Scholar
  4. 4.
    Freedman LS, Clifford C, Messina M (1990) Analysis of dietary fat, calories, body weight, and the development of mammary tumors in rats and mice: a review. Cancer Res 50(18):5710–5719PubMedGoogle Scholar
  5. 5.
    Cleary MP, Grande JP, Juneja SC, Maihle NJ (2004) Diet-induced obesity and mammary tumor development in MMTV-neu female mice. Nutr Cancer 50(2):174–180CrossRefPubMedGoogle Scholar
  6. 6.
    Kritchevsky D (2001) Caloric restriction and cancer. J Nutr Sci Vitaminol (Tokyo) 47(1):13–19Google Scholar
  7. 7.
    Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson WJ, Cohen P, Hwang D, Peterson B, Fields T, Pizzo SV, Isaacs WB (2008) Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate 68(1):11–19CrossRefPubMedGoogle Scholar
  8. 8.
    Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P (2003) Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer 89(7):1375–1382CrossRefPubMedGoogle Scholar
  9. 9.
    Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS, deCabo R (2006) Calorie restriction mimetics: an emerging research field. Aging Cell 5(2):97–108CrossRefPubMedGoogle Scholar
  10. 10.
    Kirpichnikov D, McFarlane SI, Sowers JR (2002) Metformin: an update. Ann Intern Med 137(1):25–33PubMedGoogle Scholar
  11. 11.
    Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE (1995) Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 333(9):550–554CrossRefPubMedGoogle Scholar
  12. 12.
    Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diab Care 29(2):254–258CrossRefGoogle Scholar
  13. 13.
    Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330(7503):1304–1305CrossRefPubMedGoogle Scholar
  14. 14.
    Phoenix KN, Vumbaca F, Claffey KP (2009) Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat 113(1):101–111CrossRefPubMedGoogle Scholar
  15. 15.
    Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, Thor AD (2009) Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 8(6):909–915Google Scholar
  16. 16.
    Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Y, Marchand-Brustel, Bost F (2008) The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27(25):3576–3586CrossRefPubMedGoogle Scholar
  17. 17.
    Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M (2006) Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66(21):10269–10273CrossRefPubMedGoogle Scholar
  18. 18.
    Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE, Pour PM (2001) Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 120(5):1263–1270CrossRefPubMedGoogle Scholar
  19. 19.
    Tomimoto A, Endo H, Sugiyama M, Fujisawa T, Hosono K, Takahashi H, Nakajima N, Nagashima Y, Wada K, Nakagama H, Nakajima A (2008) Metformin suppresses intestinal polyp growth in ApcMin/+mice. Cancer Sci 99(11):2136–2141CrossRefPubMedGoogle Scholar
  20. 20.
    Algire C, Zakikhani M, Blouin MJ, Shuai JH, Pollak M (2008) Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer 15(3):833–839CrossRefPubMedGoogle Scholar
  21. 21.
    Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69(19):7507–7511CrossRefPubMedGoogle Scholar
  22. 22.
    Miller FR, Miller BE, Heppner GH (1983) Characterization of metastatic heterogeneity among subpopulations of a single mouse mammary tumor: heterogeneity in phenotypic stability. Invasion Metastasis 3(1):22–31PubMedGoogle Scholar
  23. 23.
    Agarwal A, Munoz-Najar U, Klueh U, Shih SC, Claffey KP (2004) N-acetyl-cysteine promotes angiostatin production and vascular collapse in an orthotopic model of breast cancer. Am J Pathol 164(5):1683–1696PubMedGoogle Scholar
  24. 24.
    Klurfeld DM, Weber MM, Kritchevsky D (1987) Inhibition of chemically induced mammary and colon tumor promotion by caloric restriction in rats fed increased dietary fat. Cancer Res 47(11):2759–2762PubMedGoogle Scholar
  25. 25.
    Welsch CW (1992) Relationship between dietary fat and experimental mammary tumorigenesis: a review and critique. Cancer Res 52(7 Suppl):2040s–2048sPubMedGoogle Scholar
  26. 26.
    Zhu Z, Haegele AD, Thompson HJ (1997) Effect of caloric restriction on pre-malignant and malignant stages of mammary carcinogenesis. Carcinogenesis 18(5):1007–1012CrossRefPubMedGoogle Scholar
  27. 27.
    Aslakson CJ, Miller FR (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52(6):1399–1405PubMedGoogle Scholar
  28. 28.
    Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67(22):10804–10812CrossRefPubMedGoogle Scholar
  29. 29.
    Woods A, Vertommen D, Neumann D, Turk R, Bayliss J, Schlattner U, Wallimann T, Carling D, Rider MH (2003) Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis. J Biol Chem 278(31):28434–28442CrossRefPubMedGoogle Scholar
  30. 30.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108(8):1167–1174PubMedGoogle Scholar
  31. 31.
    Zhuang Y, Miskimins WK (2008) Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal 3:18CrossRefPubMedGoogle Scholar
  32. 32.
    Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67(14):6745–6752CrossRefPubMedGoogle Scholar
  33. 33.
    Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827CrossRefPubMedGoogle Scholar
  34. 34.
    Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8(12):1369–1375CrossRefPubMedGoogle Scholar
  35. 35.
    Kwan ML, Kushi LH, Weltzien E, Maring B, Kutner SE, Fulton RS, Lee MM, Ambrosone CB, Caan BJ (2009) Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors. Breast Cancer Res 11(3):R31CrossRefPubMedGoogle Scholar
  36. 36.
    Yang XR, Sherman ME, Rimm DL, Lissowska J, Brinton LA, Peplonska B, Hewitt SM, Anderson WF, Szeszenia-Dabrowska N, Bardin-Mikolajczak A, Zatonski W, Cartun R, Mandich D, Rymkiewicz G, Ligaj M, Lukaszek S, Kordek R, Garcia-Closas M (2007) Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 16(3):439–443CrossRefPubMedGoogle Scholar
  37. 37.
    Liu B, Z Fan, SM Edgerton, XS Deng, IN Alimova, SE Lind, and AD Thor (2009) Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 8(13):2031–2040Google Scholar
  38. 38.
    Kari FW, Dunn SE, French JE, Barrett JC (1999) Roles for insulin-like growth factor-1 in mediating the anti-carcinogenic effects of caloric restriction. J Nutr Health Aging 3(2):92–101PubMedGoogle Scholar
  39. 39.
    Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40(8-9):685–693CrossRefPubMedGoogle Scholar
  40. 40.
    Pollak M (2009) Do cancer cells care if their host is hungry? Cell Metab 9(5):401–403CrossRefPubMedGoogle Scholar
  41. 41.
    Pollak M (2009) Macronutrient intake and cancer: how does dietary restriction influence tumor growth and why should we care? Cancer Prev Res 2(8):698–701CrossRefGoogle Scholar
  42. 42.
    Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N (2008) Leptin signaling in breast cancer: an overview. J Cell Biochem 105(4):956–964CrossRefPubMedGoogle Scholar
  43. 43.
    Hou WK, Xu YX, Yu T, Zhang L, Zhang WW, Fu CL, Sun Y, Wu Q, Chen L (2007) Adipocytokines and breast cancer risk. Chin Med J (Engl) 120(18):1592–1596Google Scholar
  44. 44.
    Rose DP, Komninou D, Stephenson GD (2004) Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5(3):153–165CrossRefPubMedGoogle Scholar
  45. 45.
    Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287(3):356–359CrossRefPubMedGoogle Scholar
  46. 46.
    Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB (2003) The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 163(4):427–436CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Kathryn N. Phoenix
    • 1
  • Frank Vumbaca
    • 1
  • Melissa M. Fox
    • 1
  • Rebecca Evans
    • 1
  • Kevin P. Claffey
    • 1
  1. 1.Center for Vascular Biology, Department of Cell BiologyUniversity of Connecticut Health CenterFarmingtonUSA

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