Breast Cancer Research and Treatment

, Volume 64, Issue 3, pp 287–296

Effect of Melatonin and Linolenic Acid on Mammary Cancer in Transgenic Mice with c-neu Breast Cancer Oncogene

  • Ghanta N. Rao
  • Elizabeth Ney
  • Ronald A. Herbert
Conference Report

Abstract

Breast cancer is one of the most common cancers and is a leading cause of mortality in women. The TG.NK transgenic mouse line expresses the c-neu breast cancer oncogene under the control of a MMTV promoter and appears to be a useful animal model for evaluation of intervention strategies to delay/prevent breast cancer. Fiber-rich nonpurified diet (NTP-2000) and some retinoid analogues have been shown to significantly delay the development of mammary cancer in the TG.NK model. Four-week-old hemizygous TG.NK female mice with MMTV/c-neu oncogene fed NTP-2000 diet were gavaged with 0.05–0.2 ml of flaxseed oil as the source of ω-3 rich PUFA, or melatonin at 50–200 mg/kg or a combination of 0.10 ml flaxseed oil and 50 mg/kg melatonin in a gavage volume of 0.2 ml per mouse with corn oil as the vehicle for 30 weeks. The time course of the mammary tumor incidence pattern was advanced by flaxseed oil compared to the control. At the high dose (0.2 ml) of flaxseed oil, when the ω-6: ω-3 PUFA ratio was closer to 1, there was some delay in the growth of mammary tumors. Melatonin delayed the appearance of palpable tumors and the growth of the tumors with a dose-related statistically significant negative trend for the incidence of tumors. The combination of flaxseed oil and melatonin caused a significant decrease in the number of tumors and tumor weight per mouse compared to the control and to flaxseed oil but not to melatonin alone. Flaxseed oil may delay the growth of mammary tumors if the ω-6:ω-3 PUFA ratio of fat consumed is closer to 1. Melatonin has the potential to markedly delay the appearance of palpable mammary tumors. Studies are in progress with the TG.NK mouse model to understand the histological and molecular changes associated with the dose-response pattern of mammary tumor incidence and growth after treatment with a broad range of doses of melatonin.

breast cancer c-neu transgenic mice melatonin linolenic acid flaxseed oil IGF-1 concentrations 

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References

  1. 1.
    Miller BA, Ries LAG, Hankey BF, Kosary CL, Harras A, Devesa SS, Edwards BK (eds): SEER Cancer Statistics Review: 1973–1990. National Cancer Institute. NIH Pub No 93-2789, 1993Google Scholar
  2. 2.
    Clarke R: Animal models of breast cancer: Their diversity and role in biomedical research. Breast Cancer Res Treat 39: 1-6, 1996Google Scholar
  3. 3.
    Amundadottir TL, Merlino G, Dickson RB: Transgenic mouse models for breast cancer. Breast Cancer Res Treat 39: 119-135, 1996Google Scholar
  4. 4.
    Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P: Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54: 105-115, 1988Google Scholar
  5. 5.
    Tennant RW, Rao GN, Russfield A, Seilkop S, Braun AG: Chemical effects in transgenic mice bearing oncogenes expressed in mammary tissue. Carcinogenesis 14: 29-35, 1993Google Scholar
  6. 6.
    Rao GN, Ney E, Herbert RA: Influence of diet on mammary cancer in transgenic mice bearing oncogene expressed in mammary tissue. Breast Cancer Res Treat 45: 149-158, 1997Google Scholar
  7. 7.
    Moon RC, Mehta RG, Detrisac CJ: Retinoids as chemopreventive agents for breast cancer. Cancer Detect Prev 16: 73-79, 1992Google Scholar
  8. 8.
    Moon RC, Mehta RG, Rao KVN: Retinoids and cancer in experimental animals. In: Sporn M.B., Roberts A.B., and Goodman D.S. (eds), The Retinoids. 2nd edn, Raven Press, New York, 1994, pp 573-595Google Scholar
  9. 9.
    Rao GN, Ney E, Herbert RA: Effect of retinoid analogues on mammary cancer in transgenic mice with c-neu breast cancer oncogene. Breast Cancer Res Treat 48: 265-271, 1998Google Scholar
  10. 10.
    Rao GN, Ney E, Herbert RA: Changes associated with delay of mammary cancer by retinoid analogues in transgenic mice bearing c-neu oncogene. Breast Cancer Res Treat 58: 241-254, 1999Google Scholar
  11. 11.
    Gray GE, Pike MC, Henderson BE: Breast-cancer incidence and mortality rates in different countries in relation to known risk factors and dietary practices. Br J Cancer 39: 1-7, 1979Google Scholar
  12. 12.
    Rao GN: Influence of diet on Tumors of Hormonal Tissues. In: Huff J, Boyd J, Barrett J.C. (eds), Cellular and Molecular Mechanisms of Hormonal Carcinogenesis: Environmental Influences. Wiley-Liss, New York, 1996, pp 41-56Google Scholar
  13. 13.
    Freedman LS, Clifford C, Messina M: Analysis of dietary fat, calories, body weight and the development of mammary tumors in rats and mice: a review, Cancer Res 50: 5710-5719, 1990Google Scholar
  14. 14.
    Cave WT Jr: Omega-3 polyunsaturated fatty acids in rodent models of breast cancer. Breast Cancer Res Treat 46: 239-246, 1997Google Scholar
  15. 15.
    Sanders TAB, Vickers M, Hainmes AP: Effect on blood lipids and haemostasis of a supplement of cod-liver oil, rich in eicosapentaenoic acid and decosahexaenoic acids in healthy young men. Clin Sci 61: 317-324, 1981Google Scholar
  16. 16.
    Fernandes G, Venkatraman JT: Role of omega-3 fatty acids in health and disease. Nutr Res 13: s19-s45, 1993Google Scholar
  17. 17.
    Reiter RJ: The pineal and its hormones in the control of reproduction in mammals. Endocrine Rev 1: 109-131, 1980Google Scholar
  18. 18.
    Blask DE, Wilson ST, Zalatan F: Physiological melatonin inhibition of human breast cancer cell growth in vitro: Evidence for a glutathione-mediated pathway. Cancer Res 57: 1909-1914, 1997Google Scholar
  19. 19.
    Blask DE: Melatonin in oncology. In: Yu H. S. and Reiter R. J. (eds), Melatonin, Biosynthesis, Physiological Effects, and Clinical Applications, Boca Raton, FL: CRC Press, 1993, pp 447-475Google Scholar
  20. 20.
    Barchas J, DaCosta F, Spector S: Acute pharmacology of melatonin. Nature 214: 919-920, 1967Google Scholar
  21. 21.
    RTECS. Registry of Toxic Effects of Chemical Substances—on line. National Institute of Occupational Safety, US Department of Health Human Services. RTECS Number: AC5955000, 1999Google Scholar
  22. 22.
    Friedl A, Jordan VC, Pollak M: Suppression of serum insulin-like growth factor-1 levels in breast cancer patients during adjuvant tamoxifen therapy. Eur J Cancer 29A: 1368-1372, 1993Google Scholar
  23. 23.
    Kazer RR: Insulin resistance, insulin-like growth factor-1 and breast cancer: a hypothesis. Int J Cancer 62: 403-406, 1995Google Scholar
  24. 24.
    Dunn SE, Kari FW, French J, Leininger JR, Travlos G, Wilson R, Barrett JC: Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation and tumor progression in p53-deficient mice. Cancer Res 57: 4667-4672, 1997Google Scholar
  25. 25.
    Taketo M, Schroeder AC, Mobraaten LE, Gunning KB, Hanten G, Fox RR, Rodrick TH, Stewart CL, Lilly F, Hansen CT: FVB/N: an inbred mouse strain preferable for transgenic analyses. Proc Natl Acad Sci USA 88: 2065-2069, 1991Google Scholar
  26. 26.
    Webster MA, Muller WJ: Mammary tumorigenesis and metastasis in transgenic mice. Sem Cancer Biol 5: 69-76, 1994Google Scholar
  27. 27.
    National Research Council: Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington DC 1996Google Scholar
  28. 28.
    Rao GN: New nonpurified diet (NTP-2000) for rodents in the National Toxicology Program's toxicology and carcinogenesis studies. J Nutr 127: 842s-846s, 1997Google Scholar
  29. 29.
    Rao GN: New diet (NTP-2000) for rats in the National Toxicology Program toxicology and carcinogenecity studies. Fundam Appl Toxicol 32: 102-108, 1996Google Scholar
  30. 30.
    Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE: Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50: 219-244, 1966Google Scholar
  31. 31.
    Busby WH, Snyder DK, Clemson DR: Radioimmunoassay of a 26,000-Dalton plasma insulin-like growth factor-binding protein: Control by nutritional variables. J Clin Endocrinol Metab 67: 1225-1230, 1988Google Scholar
  32. 32.
    Kenney NJ, Smith GH, Rosenberg K, Cutler ML, Dickson RB: Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in mouse mammary gland. Cell Growth Differ 7: 1769-1781, 1996Google Scholar
  33. 33.
    Steel RGD, Torrie JH: Principles and Procedures of Statistics: A Biometrical Approach. 3rd edn, McGraw-Hill, New York, 1997, pp 95-100, 195 and 558Google Scholar
  34. 34.
    Cox DR, Oakes D: Analysis of Survival Data. Chapman and Hall, New York, 1984, pp 104-107Google Scholar
  35. 35.
    Hollander M, Wolfe DA: Nonparametric Statistical Methods. Wiley, New York, 1999, pp 68-7, 185–194 and 363Google Scholar
  36. 36.
    Koch GG, Atkinson SS, Stokes ME: Poisson regression. In: Kotz S, Johnson NL, Read CB (eds), Encyclopedia of Statistical Sciences (Vol 7). Wiley, New York, 1986, pp 32-41Google Scholar
  37. 37.
    Agresti A: Categorical Data analysis. Wiley, New York, 1990Google Scholar
  38. 38.
    Pirie W: Jonckheere tests for ordered alternatives. In: Kotz S, Johnson NL, Read CB (eds), Encyclopedia of Statistical Sciences Vol 4, Wiley, New York, 1983, pp 315-318Google Scholar
  39. 39.
    Fernandes G, Chandrasekar B, Troyer DA, Venkatraman JT, Good RA: Dietary lipids and caloric restriction affect mammary tumor incidence and gene expression in mouse mammary tumor virus/v-Ha-ras transgenic mice. Proc Natl Acad Sci 92: 6494-6498, 1995Google Scholar
  40. 40.
    Simonsen N, van't Veer P, Strain JJ, Martin-Moreno JM, Huttuen JK, Navajas JFC, Martin BC, Thamm M, Kardinaal AFM, Kok FJ, Kohlmeier L: Adipose tissue omega-3 and omega-6 fatty acid content and breast cancer in the EURAMIC study. Am J Epidemiol 147: 342-352, 1998Google Scholar
  41. 41.
    Shah PN, Mhatre MC, Kothari L: Effect of melatonin on mammary carcinogenesis in intact and pinealectomized rats in varying photoperiods. Cancer Res 44: 3403-3408, 1984Google Scholar
  42. 42.
    Poeggeler B, Reiter RJ, Hardeland R, Sewerynek E, Melchiorri D, Barlow-Walden LR: Melatonin, a mediator of electron transfer and repair reactions; acts synergistically with the chain-breaking antioxidants ascorbate, trolox, and glutathione. Neuroendocrinol Lett 19: 87-92, 1995Google Scholar
  43. 43.
    Blask DE, Sauer LA, Dauchy RT, Holowachuk EW, Ruhoff MS, Kopff HS: Melatonin inhibition of cancer growth in vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transduction events. Cancer Res 59: 4693-4701, 1999Google Scholar
  44. 44.
    Nordlund JJ, Lerner AB: The effects of melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab 45: 768-774, 1977Google Scholar
  45. 45.
    Robinson WA, Dreiling L, Gonzalez R, Balmer C: Treatment of human metastatic malignant melanoma with high dose oral melatonin. In: Fraschini F, Reiter RJ, Stankov B (eds), The Pineal Gland and its Hormones: Fundamental and Clinical Perspectives, Plenum Press, New York, 1995, pp 219-225Google Scholar
  46. 46.
    Silman RE: Melatonin: a contraceptive for the nineties. Eur J Obstet Gynecol Reprod Biol 49: 3-9, 1993Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Ghanta N. Rao
  • Elizabeth Ney
  • Ronald A. Herbert

There are no affiliations available

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