Breast Cancer Research and Treatment

, Volume 77, Issue 3, pp 205–215

Genetically Obese MMTV-TGF-α/LepobLepob Female Mice do not Develop Mammary Tumors

  • Margot P. Cleary
  • Frederick C. Phillips
  • Susan C. Getzin
  • Tina L. Jacobson
  • Michelle K. Jacobson
  • Trace A. Christensen
  • Subhash C. Juneja
  • Joseph P. Grande
  • Nita J. Maihle


Elevated body weight is a risk factor for postmenopausal breast cancer and is associated with increased incidence of spontaneous and chemically induced mammary tumors (MTs) in rodents. In this study, genetically obese LepobLepob female mice that overexpress human TGF-α (transforming growth factor-alpha) were used to assess the role of body weight on oncogene-induced MT development in comparison to lean counterparts. MMTV (mouse mammary tumor virus)-TGF-α and Lep strain mice were crossed to produce TGF-α/Lep+Lep+ (homozygous lean), TGF-α/Lep+Lepob (heterozygous lean) and TGF-α/LepobLepob (homozygous obese) genotypes. Body weights were determined weekly and mice palpated for the presence of MTs until 104 weeks of age. Despite their significantly higher body weight, obese TGF-α/LepobLepob mice failed to develop MTs. MTs were detected between 48 and 104 weeks of age for 26/39 TGF-α/Lep+Lepob mice and for 19/38 TGF-α/Lep+Lep+ mice between 67 and 104 weeks of age. Although MT incidence was not statistically different between the lean groups, age of MT detection tended to be younger for TGF-α/Lep+Lepob mice (p < 0.09). There were significant effects of both genotype and MTs on final body weight, that is, TGF-α/Lep+Lepob mice weighed more than homozygous lean mice, and mice with MTs weighed more than those without MTs. TGF-α/LepobLepob mice are not a good model to evaluate the effect of body weight on MT development possibly due to leptin deficiency. However, the finding that increased body weight is associated with increased oncogene-induced MT development within the normal weight range provides experimental support for the role of body weight in breast cancer.

body weight heterozygous leptin mammary tumors obesity ovarian tumors postmenopausal breast cancer transgenic mice 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, Hennekens CH, Rosner B, Speizer FE, Willett WC: Dual effects of weight and weight gain on breast cancer risk. JAMA 278: 1407-1411, 1997Google Scholar
  2. 2.
    Negri E, La Vecchia C, Bruzzi P, Dardanoni G, Decarli A, Palli D, Parazzini F, Del Turco MR: Risk factors for breast cancer: pooled results from three Italian case-control studies. Am J Epidemiol 128: 1207-1215, 1988Google Scholar
  3. 3.
    La Vecchia C, Negri E, Franceschi S, Talamini R, Bruzzi P, Palli D, Decarli A: Body mass index and post-menopausal breast cancer: an age-specific analysis. Brit J Cancer 75: 441-444, 1997Google Scholar
  4. 4.
    Cold S, Hansen S, Overvad K, Rose, C: A woman's build and the risk of breast cancer. Eur J Cancer 34: 1163-1174, 1998Google Scholar
  5. 5.
    Cleary MP, Maihle NJ: The role of body mass index in the relative risk of developing premenopausal versus postmenopausal breast cancer. Proc Soc Exp Biol Med 216: 28-43, 1997Google Scholar
  6. 6.
    Waxler SH, Tabar P, Melcher LP: Obesity and the time of appearance of spontaneous mammary carcinoma in C3H mice. Cancer Res 13: 276-278, 1953Google Scholar
  7. 7.
    Waxler SH: Obesity and cancer susceptibility in mice. Am J Clin Nutr 8: 760-766, 1960Google Scholar
  8. 8.
    Seilkop SK: The effect of body weight on tumor incidence and carcinogenicity testing in B6C3F1 mice and F344 rats. Fundam Appl Toxicol 24: 247-259, 1995Google Scholar
  9. 9.
    Haseman JK, Bourbina J, Eustis SL: Effect of individual housing and other experimental design factors on tumor incidence in B6C3F1 mice. Fundam Appl Toxicol 23: 44-52, 1994Google Scholar
  10. 10.
    Heston WE, Vlahakis G: Genetic obesity and neoplasia. J Natl Cancer Inst 29: 197-209, 1962Google Scholar
  11. 11.
    Wolff GL, Kodell RL, Cameron AM: Accelerated appearance of chemically induced mammary carcinomas in obese yellow (Avy/A) (BALB/c Xvy) F1 hybrid mice. J Tox Environ Health 10: 131-142, 1982Google Scholar
  12. 12.
    Klurfeld DM, Lloyd LM, Welch CB, Davis MJ, Tulp OL, Kritchevsky D: Reduction of enhanced mammary carcinogenesis in LA/N-cp (corpulent) rats by energy restriction. Proc Soc Exp Biol Med 196: 381-384, 1991Google Scholar
  13. 13.
    Glinsky GV, Price JE, Glinsky VV, Mossine VV, Kiriakova G, Metcalf JB: Inhibition of human breast cancer metastasis in nude mice by synthetic glycoamines. Cancer Res 56: 5319-5324, 1996Google Scholar
  14. 14.
    Rose DP, Hatala MA, Connolly JM, Rayburn J: Effects of diets containing different levels of linoleic acid on human breast cancer growth and lung metastasis in nude mice. Cancer Res 53: 4686-4690, 1993Google Scholar
  15. 15.
    Taylor-Papadimitriou J, Berdichevsky F, D'souza B, Burchell J: Human models of breast cancer. Cancer Surv 16: 59-78, 1993Google Scholar
  16. 16.
    Dao TL: Carcinogenesis of mammary gland in rat. Prog Exp Tumor Res 5: 157-216, 1964Google Scholar
  17. 17.
    Russo J, Russo IH: Experimentally induced mammary tumors in rats. Breast Cancer Res Treat 39: 7-20, 1996Google Scholar
  18. 18.
    Archer FL, Orlando RA: Morphology, natural history, and enzyme patterns in mammary tumors of the rat induced by 7,12-dimethylbenz(a)anthracene. Cancer Res 28: 217-224, 1968Google Scholar
  19. 19.
    Matsui Y, Halter SA, Holt JT, Hogan BLM, Coffey RJ: Development of mammary hyperplasia and neoplasia in MMTVTGFα transgenic mice. Cell 61: 1147-1155, 1990Google Scholar
  20. 20.
    Halter SA, Dempsey PJ, Matsui S, Stokes K, Graves-Deal R, Hogan BLM, Coffey RJ: Distinctive patterns of hyperplasia in transgenic mice with mouse mammary tumor virus transforming growth factor-α. Am J Pathol 140: 1131-1146, 1992Google Scholar
  21. 21.
    Ip C: Controversial issues of dietary fat and experimental mammary carcinogenesis. Prev Med 22: 728-737, 1993Google Scholar
  22. 22.
    Welsch CW, House JL, Herr BL, Eliasberg SJ, Welsch MA: Enhancement of mammary carcinogenesis by high levels of dietary fat: a phenomenon dependent on ad libitum feeding. J Natl Cancer Inst 82: 1615-1620, 1990Google Scholar
  23. 23.
    Willett WC: Dietary fat intake and cancer risk: a controversial and instructive story. Sem Cancer Biol 8: 245-253, 1998Google Scholar
  24. 24.
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425-432, 1994Google Scholar
  25. 25.
    Chung WK, Belfi K, Chua M, Wiley J, Mackintosh R, Nicolson M, Boozer CN, Leibel RL: Heterozygosity for Lepob or Leprdb affects body composition and leptin homeostasis in adult mice. Am J Physiol 274: R985-R990, 1998Google Scholar
  26. 26.
    Sakai S, Mizuno M, Harigaya T, Yamamoto K, Mori T, Coffey RJ, Nagasawa H: Cause of failure of lactation in mouse mammary tumor virus/human transforming growth factor α transgenic mice. Proc Soc Exp Biol Med 205: 236-242, 1994Google Scholar
  27. 27.
    Cleary MP, Bergstrom HM, Dodge TL, Getzin SC, Jacobson MK, Phillips FC: Restoration of fertility in young obese (Lepob Lepob) male mice with low dose recombinant mouse leptin treatment. Int J Obesity 25: 95-97, 2001Google Scholar
  28. 28.
    Laud K, Gourdou I, Pessemesse L, Peyrat JP, Dijane J: Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line. Mol Cell Endocrinol 188: 219-226, 2002Google Scholar
  29. 29.
    Hu X, Juneja SC, Maihle NJ, Cleary MP: Leptin-A growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94: 1704-1711, 2002Google Scholar
  30. 30.
    Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis JR, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP: Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84: 491-495, 1996Google Scholar
  31. 31.
    Montague CT, Farooqui AA, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S: Congenital leptin deficiency is associated with severe earlyonset obesity in humans. Nature 387: 903-908, 1997Google Scholar
  32. 32.
    Carlsson B, Lindell K, Gabrielsson B, Karlsson C, Bjarnason R, Westphal O, Karlsson U, Sjöström L, Carlsson LMS: Obese (ob) gene defects are rare in human obesity. Obes Res 5: 30-35, 1997Google Scholar
  33. 33.
    Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD: A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 18: 213-215, 1998Google Scholar
  34. 34.
    Farooqui IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R, Jebb SA, Lip GYH, O'Rahilly S: Partial leptin deficiency and human adiposity. Nature 414: 34-35, 2001Google Scholar
  35. 35.
    Clarke R: Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models. Breast Cancer Res Treat 46: 255-278, 1997Google Scholar
  36. 36.
    Blaakaer J, Baeksted M, Micic S, Albrectsen P, Rygaard J, Bock J: Gonadotropin-releasing hormone agonist suppression of ovarian tumorigenesis in mice of theWx/Wv genotype. Biol Reprod 53: 775-779, 1995Google Scholar
  37. 37.
    Kananen K, Rilianawati Paukku T, Markkula M, Rainio EM, Huhtanemi I: Suppression of gonadotropins inhibits gonadal tumorigenesis in mice transgenic for the mouse inhibin asubunit promoter/simian virus 40 T-antigen fusion gene. Endocrinology 138: 3521-3531, 1997Google Scholar
  38. 38.
    Matzuk MM, Finegold MJ, Su JGJ, Hsueh AJW, Bradley A: α-Inhibin is a tumor-suppressor gene with gonadal specificity in mice. Nature 360: 313-319, 1992Google Scholar
  39. 39.
    Coleman DL: Obesity genes: beneficial effects in heterozygous mice. Science 203: 663-665, 1979Google Scholar
  40. 40.
    Shimizu H, Shimomura Y, Hayashi R, Ohtani K, Sato N, Mori M: Serum leptin concentration is associated with total body fat mass, but not abdominal fat distribution. Int J Obesity 21: 536-541, 1997Google Scholar
  41. 41.
    Ahren B, Mansson S, Gingerich RL, Havel PJ: Regulation of plasma leptin in mice: influence of age, high-fat diet, and fasting. Am J Physiol 273: R113-R120, 1997Google Scholar
  42. 42.
    Havel PJ, Kasim-Karakas S, Mueller W, Johnson PR, Gingerich RL, Stern JS: Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss. J Clin Endocrinol Metab 81: 4406-4413, 1996Google Scholar
  43. 43.
    Ostlund Jr RE, Yang JW, Klein S, Gingerich R: Relation between plasma leptin concentration and body fat, gender, diet, age, and metabolic covariates. J Clin Endocrinol Metab 81: 3909-3913, 1996Google Scholar
  44. 44.
    Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS: Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1: 1311-1314, 1995Google Scholar
  45. 45.
    Edman CD, Aiman EJ, Porter JC, MacDonald PC: Identification of the estrogen product of extraglandular aromatization of plasma androstenedione. Am J Obstet Gynecol 130: 439-447, 1978Google Scholar
  46. 46.
    MacDonald PC, Edman CD, Hemsell DL, Porter JC, Siiteri PK: Effect of obesity on conversion of plasma androstenedione to estrone in postmenopausal women with and without endrometrial cancer. Am J Obstet Gynecol 130: 448-455, 1978Google Scholar
  47. 47.
    Stoll BA: Obesity, social class and western diet: a link to breast cancer prognosis. Eur J Cancer 32A: 1293-1295, 1996Google Scholar
  48. 48.
    Kaaks R: Nutrition, hormones, and breast cancer: is insulin the missing link? Cancer Causes Control 7: 605-625, 1996Google Scholar
  49. 49.
    Bruning PF, Bonfrer JMG, Van Noord PAH, Hart AAM, de Jong-Bakker M, Nooden WJ: Insulin resistance and breastcancer risk.Int J Biochem 52: 511-516, 1992Google Scholar
  50. 50.
    Heuson JC, Legros N: Influence of insulin deprivation on growth of the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats subjected to alloxan diabetes and food restriction. Cancer Res 32: 226-232, 1972Google Scholar
  51. 51.
    Heuson JC, Legros N, Heimann R: Influence of insulin administration on growth of the 7,12-dimethylbenz(a)anthraceneinduced mammary carcinoma in intact, oophorectomized, and hypophysectomized rats. Cancer Res 32: 233-238, 1972Google Scholar
  52. 52.
    Jatoi A, Cleary MP, Tee CM, Nguyen PL: Weight gain does not preclude increased ubiquitin conjugation in skeletal muscle: an exploratory study in tumor-bearing mice. Ann Nutr Metab 45: 116-120, 2001Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Margot P. Cleary
    • 1
  • Frederick C. Phillips
    • 1
  • Susan C. Getzin
    • 1
  • Tina L. Jacobson
    • 1
  • Michelle K. Jacobson
    • 1
  • Trace A. Christensen
    • 2
  • Subhash C. Juneja
    • 2
  • Joseph P. Grande
    • 3
  • Nita J. Maihle
    • 2
  1. 1.The Hormel InstituteUniversity of MinnesotaAustin
  2. 2.Department of Biochemistry and Molecular BiologyMayo ClinicRochesterUSA
  3. 3.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA

Personalised recommendations