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Breast Cancer Research and Treatment

, Volume 72, Issue 1, pp 33–43 | Cite as

Tumor Prevention by 9-Cis-Retinoic Acid in the N-Nitroso-N-Methylurea Model of Mammary Carcinogenesis is Potentiated by the Pineal Hormone Melatonin

  • S. Nowfar
  • S.R. Teplitzky
  • K. Melancon
  • T.L. Kiefer
  • Q. Cheng
  • P.D. Dwivedi
  • E.D. Bischoff
  • K. Moroz
  • M.B. Anderson
  • J. Dai
  • L. Lai
  • L. Yuan
  • S.M. Hill
Conference Report

Abstract

Our laboratory has demonstrated that treatment of MCF-7 breast cancer cells with melatonin (Mlt) followed 24 h later with physiological concentrations of all-trans retinoic acid (atRA) results in apoptosis. These studies were extended into trials using the N-nitroso-N-methylurea (NMU)-induced rat mammary tumor model. Initial studies conducted by feeding the animals 9-cis-retinoic acid (9cRA in the chow) and administering melatonin by subcutaneous injection in the late afternoon demonstrated that the combination of Mlt and 9cRA was able to significantly prevent tumor development, and that the combination was more efficacious that either Mlt or 9cRA alone. In this report, we conducted studies to determine if lower doses of 9cRA could be used in combination with Mlt while still maintaining anti-tumor activity and if the route of administration of 9cRA (bolus (gavage) v.s. chronic (chow) routes) affected its interaction with Mlt. The studies presented here demonstrate that significantly reduced doses of 9cRA can be used in combination with Mlt while maintaining anti-tumor efficacy. Furthermore, our studies demonstrate that 9cRA is equally effective when it is administered chronically (chow) or as a bolus (gavage). These data demonstrate that the combined use of Mlt and 9cRA produces additive or synergistic effects, which are more efficacious than 9cRA alone. This combination of Mlt and 9cRA could be a potentially useful clinical treatment regimen for breast cancer since it allows the use of lower doses of retinoic acid, thus, avoiding the toxic side effects associated with the use of high dose retinoids.

breast cancer chemoprevention melatonin N-nitroso-N-methylurea 9-cis retinoic acid 

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References

  1. 1.
    Kardinal CG: Endocrine therapy of breast cancer. In: Donegan WL, Spratt JS, (eds) Cancer of the Breast. 4th edn, W.B. Saunders Company, Philadelphia, 1995, pp 534–580Google Scholar
  2. 2.
    McGuire WL, Osborne CK, Clark GM, Knight WA: Steroid hormone receptors and carcinoma of the breast. Am J Physiol 243: E99–E102, 1982Google Scholar
  3. 3.
    Edwards DP, Chamness GC, McGuire WL: Estrogen and progesterone receptors in breast cancer. Biochem Biophys Acta 560: 457–486, 1979Google Scholar
  4. 4.
    Lotan R: Different susceptibilities of human melanoma and breast carcinoma cell lines to retinoic acid-induced growth inhibition. Cancer Res 39: 1014–1019, 1979Google Scholar
  5. 5.
    Smith MA, Parkinson DR, Cheson BD, Friedman MA: Retinoids in cancer therapy. J Clin Oncol 10: 839–864, 1992Google Scholar
  6. 6.
    Lotan R: Retinoids in cancer chemoprevention. FASEB J 10: 1031–1039, 1996Google Scholar
  7. 7.
    Moon RC, Grubbs CJ, Sporn MB, Goodman DG: Retinyl acetate inhibits mammary carcinogenesis induced by N-methyl-N-nitrosourea. Nature 267: 620–621, 1977Google Scholar
  8. 8.
    Benbrook D, Lernhardt E, Pfahl M: A new retinoic acid receptor identified from a hepatocellular carcinoma Nature 333: 669–672, 1988Google Scholar
  9. 9.
    Petkovich M, Brand NJ, Krust A, Chambon P: A human retinoic acid receptor which belongs to the family of nuclear orphan receptors. Nature 330: 444–450, 1987Google Scholar
  10. 10.
    Krust A, Kastner P, Petkovich M, Zelent A, Chambon P: A third human retinoic acid receptor, hRARγ. Proc Natl Acad Sci USA 86: 5310–5314, 1989Google Scholar
  11. 11.
    Zhang X, Pfahl M: Regulation of retinoid and thyroid hormone action through homodimeric and heterodimeric receptors. Trends Endocrinol Metab 4: 156–162, 1993Google Scholar
  12. 12.
    Giguere V: Retinoic acid receptors and cellular retinoid binding proteins: complex interplay in retinoid signaling. Endocrinol Rev 15: 61–79, 1994Google Scholar
  13. 13.
    Lammer EJ, Chen DT, Hoar RM, Angish ND, Benke PJ, Braun JT, Curry CT, Fernhoff PM, Grix AW, Lott IT, Richard JM, Sun S: Retinoic acid embryopathy. N Engl J Med 313: 837–841, 1985Google Scholar
  14. 14.
    Armstrong RB, Ashenfelter KO, Eckhoff C, Levin AA, Shapiro SS: General and reproductive toxicology of retinoids. In: Sporn MB, Roberts AB, Goodman DS (eds) The Retinoids: Biology, Chemistry, and Medicine. Raven Press, New York, 1994, pp 545–572Google Scholar
  15. 15.
    Aubert CH, Janiaud P, Leclavez J: Effect of pinealectomy and melatonin on mammary tumor growth in Sprague-Dawley rats under different conditions of lighting. J Neural Transm 47: 121–130, 1980Google Scholar
  16. 16.
    Tamarkin L, Cohen M, Roselle D, Reichert C, Lippman M, Chabner B: Melatonin inhibition and pinealectomy enhancement of 7-12 dimethylbenz(a)anthracene-induced mammary tumors in the rat. Cancer Res 41: 4432–4436, 1981Google Scholar
  17. 17.
    Blask DE: The pineal: an oncostatic gland? In: Reiter RJ, (ed) The Pineal Gland. Raven Press, New York, 1984, 253–284.Google Scholar
  18. 18.
    Blask DE, Hill SM, Orstead KM, Massa JS: Inhibitory effects of the pineal hormone melatonin and underfeeding during the promotional phase of 7,12-dimethylbenzantracene (DMBA)-induced mammary tumorigenesis. J Neural Transm 67: 125–138, 1986Google Scholar
  19. 19.
    Blask DE, Pelletier DB, Hill SM, Lemus-Wilson A, Grosso DS, Wilson ST, Wise ME: Pineal melatonin inhibition of tumor promotion in the N-nitroso-N-methylurea model of mammary carcinogenesis: potential involvement of antiestrogenic mechanisms in vivo. J Cancer Res Clin Oncol 117: 526–532, 1991Google Scholar
  20. 20.
    Hill SM, Blask DE: Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 48: 6121–6126, 1988Google Scholar
  21. 21.
    Cos S, Blask DE: Effects of the pineal hormone melatonin on the anchorage-independent growth of human breast cancer cells (MCF-7) in a clonogenic culture system. Cancer Lett 50: 115–119, 1990Google Scholar
  22. 22.
    Cos S, Blask DE, Lemus-Wilson A, Hill SM: Effects of melatonin on the cell cycle kinetics and estrogen-rescue of MCF-7 human breast cancer cells in culture. J Pineal Res 10: 36–42, 1991Google Scholar
  23. 23.
    Rato AG, Pedrero JG, Martinez MA, Del Rio B, Lazo PS, Ramos S: Melatonin blocks the activation of estrogen receptor for DNA binding. FASEB J 13: 857–868, 1999Google Scholar
  24. 24.
    Ram PT, Kiefer TL, Silverman M, Song Y, Brown GM, Hill SM: Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors. Mol Cell Endocrinol 141: 53–64, 1998Google Scholar
  25. 25.
    Dai J, Ram PT, Yuan L, Spriggs LL, Hill SM: Transcriptional repression of RORβ activity in human breast cancer cells by melatonin. Mol Cell Endocrinol 176: 111–120, 2001Google Scholar
  26. 26.
    Eck-Enriquez K, Kiefer TL, Spriggs LL, Hill SM: Pathways through which a regimen of melatonin and retinoic acid induces apoptosis in MCF-7 human breast cancer cells. Breast Cancer Res Treat 61: 229–239, 2000Google Scholar
  27. 27.
    Eck, M, Yuan L, Duffy L, Ram PT, Ayettey S, Chen I, Cohn CS, Reed JC, Hill SM: A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells. Br J Cancer 77: 2129–2137, 1998Google Scholar
  28. 28.
    Teplitzky SR, Kiefer TL, Cheng Q, Dwivede PD, Moroz K, Myers L, Anderson MB, Collins A, Dai J, Yuan L, Spriggs LL, Blask DE, Hill SM: Chemoprevention of NMU-induced rat mammary carcinoma with the combination of melatonin and 9-cis-retinoic acid. Cancer Lett 168: 155–163, 2001Google Scholar
  29. 29.
    Thompson HJ, Adlakha H: Dose-responsive induction of mammary gland carcinomas by the intraperitoneal injection of 1-methyl-1-nitrosourea. Cancer Res 51: 3411–3415, 1991Google Scholar
  30. 30.
    Gottardis MM, Jordan VC: Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res 47: 4020–4024, 1987Google Scholar
  31. 31.
    Anzano MA, Byers SW, Smith JM, Peer CW, Mullen LT, Brown CC, Roberts AB, Sporn MB: Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. Cancer Res 54: 4614–4617, 1994Google Scholar
  32. 32.
    Gottardis MM, Bischoff ED, Shirley MA, Wagoner MA, Lamph WW, Heyman RA: Chemoprevention of mammary carcinoma by LGD1069 (Targretin): an RXR-selective ligand. Cancer Res 56: 5566–5570, 1996Google Scholar
  33. 33.
    Bischoff ED, Gottardis MM, Moon TE, Heyman RA, Lamph WW: Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma. Cancer Res 58: 479–484, 1998Google Scholar
  34. 34.
    Bischoff ED, Heyman RA, Lamph WW: Effect of retinoid X receptor-selective ligand LGD1069 on mammary carcinoma after tamoxifen failure. J Natl Cancer Inst 91: 2118–2123, 1999Google Scholar
  35. 35.
    Miller WH, Jakubowski A, Tong WP, Miller VA, Rigas JR, Benedetti F, Gill GM, Truglia JA, Ulm E, Shirley M: 9-cisretinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia. Blood 85: 3021–3027, 1995Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • S. Nowfar
    • 1
    • 2
  • S.R. Teplitzky
    • 3
    • 2
  • K. Melancon
    • 3
    • 2
  • T.L. Kiefer
    • 4
    • 2
  • Q. Cheng
    • 1
    • 2
  • P.D. Dwivedi
    • 1
    • 2
  • E.D. Bischoff
    • 5
  • K. Moroz
    • 6
    • 2
  • M.B. Anderson
    • 1
    • 2
  • J. Dai
    • 1
    • 2
  • L. Lai
    • 1
    • 2
  • L. Yuan
    • 1
    • 2
  • S.M. Hill
    • 1
    • 4
    • 2
  1. 1.Structural & Cellular BiologyUSA
  2. 2.Tulane Cancer CenterTulane University School of MedicineNew OrleansUSA
  3. 3.Departments of SurgeryUSA
  4. 4.Molecular & Cellular Biology Graduate ProgramUSA
  5. 5.X-Ceptor TherapeuticsSan DiegoUSA
  6. 6.PathologyUSA

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