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Hormone prevention of mammary carcinogenesis by norethynodrel-mestranol

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Summary

The observation that the susceptibility of the mammary gland to chemical carcinogenesis is inversely related to its level of hormonally induced differentiation led us to test whether treatment of virgin rats with an estrogenic-progestagenic hormone combination protected the gland against this carcinogenesis. Virgin Sprague-Dawley rats aged 45, 55, 65, or 75 days had implanted subcutaneously for 21 days a pellet containing norethynodrel-mestranol (NM) (98.5%—1.5%) at two doses, a physiological or low dose (LD) of 0.5 mg, equivalent to the dose used in Enovid® for contraception in humans, and a pharmacological or high dose (HD) of 5.0 mg. Twenty-one days after NM pellet removal, the mammary glands of 5 animals per group were examined for the number of terminal end buds (TEBs), terminal ducts (TDs), alveolar buds (ABs) and lobules, and the DNA labeling index (DNA-LI). The remaining animals received 8 mg 7,12-dimethylbenz(a) anthracene (DMBA)/100 g body weight, and tumorigenesis was evaluated at 24 weeks. The percentage of TEBs decreased with age, and further with NM treatment at both doses. Treatment did not significantly modify the percentage of TDs, but increased that of ABs in most groups. The DNA-LI of TEBs remained constant, even during aging and after treatment, whereas both aging and treatment reduced DNA-LI in TDs and ABs. Tumor incidence declined with increasing age from 75% to 44% in the 45 and 75 day-old control groups respectively. Adenocarcinoma incidence followed the same trend. NM treatment had a dose-related protective effect against development of tumors in general and of adenocarcinomas in particular. LD treatment resulted in a marginally significant reduction in adenocarcinoma incidence, whereas HD-treated animals were 0.24 times as likely as controls to develop carcinomas. There was a statistically significant correlation between the percentage of TEBs present in the gland at the time of carcinogen administration and the incidence of adenocarcinomas. It was concluded that treatment of virgin rats with the hormone combination norethynodrel-mestranol resulted in long lasting structural changes in the mammary gland which protected this organ from a subsequent carcinogenic insult.

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References

  1. Russo J, Russo IH: Biological and molecular bases of mammary carcinogenesis. Lab Invest 57: 112–137, 1987

    PubMed  Google Scholar 

  2. White E, Daling JR, Norested TL, Chu J: Rising incidence of breast cancer among young women in Washington state. J Natl Cancer Inst 79: 239–243, 1987

    PubMed  Google Scholar 

  3. MacMahon B, Cole P, Liu M, Lowe CR, Mirra AP, Ravinihar B, Salber EJ, Valaoras VG, Yuasa S: Age at first birth and breast cancer risk. Bull WHO 34: 209–221, 1970

    Google Scholar 

  4. MacMahon B: Etiology of human breast cancer. J Natl Cancer Inst 50: 21–42, 1973

    PubMed  Google Scholar 

  5. Valaoras VG, MacMahon B, Trichopoulus D, Polychrono-poulou A: Lactation and reproductive histories of breast cancer patients in greater Athens, 1965–1967. Int J Cancer 4: 340–363, 1969

    Google Scholar 

  6. Yuasa S, MacMahon B: Lactation and reproductive histories of breast cancer patients in Tokyo, Japan. Bull WHO 42: 195–204, 1970

    PubMed  Google Scholar 

  7. Salber EJ, Trichopoulos D, MacMahon B: Lactation and reproductive histories of breast cancer patients in Boston. J Natl Cancer Inst 43: 1013–1024, 1969

    PubMed  Google Scholar 

  8. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S: Breast cancer in young women and use of oral contraceptives: Possible modifying effect of formulation and age at use. Lancet 2: 926–930, 1983

    PubMed  Google Scholar 

  9. Pike MC, Henderson BE, Casagrande JT, Rosario I, Gray GE: Oral contraceptive use and early abortion as risk factors for breast cancer in young women. Br J Cancer 43: 72–76, 1981

    PubMed  Google Scholar 

  10. Hadjimichael OC, Boyle CA, Meigs JW: Abortion before first live birth and risk of breast cancer. Br J Cancer 53: 281–284, 1986

    PubMed  Google Scholar 

  11. Huggins C, Grand LC, Brillantes F: Critical significance of breast structure in the induction of mammary cancer in the rat. Proc Natl Acad Sci 45: 1294–1300, 1959

    Google Scholar 

  12. Russo IH, Russo J: Developmental stage of the rat mammary gland as determinant of its susceptibility to 7,12-dimethylbenz(a)-anthracene. J Natl Cancer Inst 61: 1439–1449, 1978

    PubMed  Google Scholar 

  13. Russo J, Russo IH: DNA labeling index and structure of the rat mammary gland as determinants of its susceptibility to carcinogenesis. J Natl Cancer Inst 61: 1451–1459, 1978

    PubMed  Google Scholar 

  14. Russo J, Russo IH: Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis. Cancer Res 40: 2677–2687, 1980

    PubMed  Google Scholar 

  15. Russo J, Tay LK, Russo IH: Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat 2: 5–73, 1982

    PubMed  Google Scholar 

  16. Russo J, Saby J, Isenberg WM, Russo IH: Pathogenesis of mammary carcinomas induced in rats by 7,12-dimethylbenz (a)anthracene. J Natl Cancer Inst 59: 435–445, 1977

    Google Scholar 

  17. Russo J, Wilgus G, Russo IH: Susceptibility of the mammary gland to carcinogenesis. I. Differentiation of the mammary gland as determinant of tumor incidence and type of lesion. Am J Pathol 96: 721–736, 1979

    PubMed  Google Scholar 

  18. Tay LK, Russo J: Effect of human chorionic gonadotropin on 7,12-dimethylbenz(a)anthracene induced DNA binding and repair synthesis by rat mammary epithelial cells. Chem Biol Interact 55: 13–21, 1985

    PubMed  Google Scholar 

  19. Russo J: Basis of cellular autonomy in the susceptibility to carcinogenesis. Toxicol Pathol 11: 149–165, 1983

    PubMed  Google Scholar 

  20. Dao TL, Bock FG, Greiner MJ: Mammary carcinogenesis by 3-methylcholanthrene. II. Inhibitory effect of pregnancy and lactation on tumor induction. J Natl Cancer Inst 25: 991–1003, 1960

    PubMed  Google Scholar 

  21. Russo J, Russo IH: Susceptibility of the mammary gland to carcinogenesis. II. Pregnancy interruption as a risk factor in tumor incidence. Am J Pathol 100: 497–512, 1980

    PubMed  Google Scholar 

  22. Russo J, Miller J, Russo IH: Hormonal Treatment Prevents DMBA-Induced Rat Mammary Carcinoma. Proc Am Assoc Cancer Res 23: 348a, 1982

  23. Russo IH, Russo J: From pathogenesis to hormone prevention of mammary carcinogenesis. Cancer Surveys 5: 649–670, 1986

    PubMed  Google Scholar 

  24. Marchant J: Influence of pregnancy and lactation on the incidence of mammary carcinoma induced with methylcho-lanthrene in female mice on the ‘IF’ strain. J Pathol Bacteriol 70: 415–418, 1955

    PubMed  Google Scholar 

  25. Marchant J: The inhibitory effect of continued lactation on the incidence of chemically-induced breast tumors in mice of the IF strain. Brit J Cancer 12: 55–61, 1958

    PubMed  Google Scholar 

  26. Tay LK, Russo J: In Vitro metabolism of 7,12-dimethyl-benz(a)-anthracene in mammary epithelial cells from rats with different susceptibilities to carcinogenesis. Carcinogenesis 4: 733–738, 1983

    PubMed  Google Scholar 

  27. Ciocca DR, Parente A, Russo J: Endocrinologic milieu and susceptibility of the rat mammary gland to carcinogenesis. Am J Pathol 109: 47–56, 1982

    PubMed  Google Scholar 

  28. Daniel CW, Silberstein GB, Strickland P: Direct action of 17 B-Estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. Cancer Res 47: 6052–6057, 1987

    PubMed  Google Scholar 

  29. Freeman CS, Topper YJ: Progesterone and glucocorticoid in relation to the growth and differentiation of mammary epithelium. J Toxicol Environ Health 4: 269–282, 1978

    PubMed  Google Scholar 

  30. Welsch CW, Clemens JA, Meites J: Effects of multiple pituitary homografts or progesterone on 7,12-dimethylbenz (a)anthracene induced mammary tumors in rats. J Natl Cancer Inst 41: 465–471, 1968

    PubMed  Google Scholar 

  31. Welsch CW, Meites J: Effects of Norethynodrel-Mestranol combination (Enovid) on development and growth of carcinogen-induced mammary tumors in female rats. Cancer 13: 601–607, 1969

    Google Scholar 

  32. Stern E, Mickey MR: Effects of a cyclic steroid contraceptive regimen on mammary gland tumor induction in rats. Brit J Cancer 23: 391–400, 1969

    PubMed  Google Scholar 

  33. Gray LA, Robertson RW: Estrogens, the pill, and the breast. In: Gallager HS (ed) Early Breast Cancer Detection and Treatment. New York, John Wiley & Sons, 1975, pp 27–36

    Google Scholar 

  34. Fasal E, Paffenbarger RS: Oral contraceptives as related to cancer and benign lesions of the breast. J Natl Cancer Inst 55: 767–773, 1975

    PubMed  Google Scholar 

  35. Taylor HB: Oral contraceptives and pathologic changes in breast. Cancer 28: 1388–1390, 1971

    PubMed  Google Scholar 

  36. Kahn RA, Baker BL: Effect of Norethynodrel alone or combined with mestranol on the mammary glands of the adult female rat. Endocrinol 75: 818–821, 1964

    Google Scholar 

  37. Russo IH, Al-Rayess M, Sabharwal S: Effect of contraceptive agents on mammary gland structure and susceptibility to carcinogenesis. Proc Am Assoc Cancer Res 26: 460a, 116, 1985

    Google Scholar 

  38. Edgren RA: The Biology of Steroidal Concentraceptives. In: Ednicer DL (ed) Contraception: The Chemical Control of Fertility. Marcel Dekker, Inc., New York, 1969, pp 23–68

    Google Scholar 

  39. Minaguchi H, Meites J: Effects of a Norethynodrel-Mestranol combination (Enovid) on hypothalamic and pituitary hormones in rats. Endocrinol 81: 826–834, 1967

    Google Scholar 

  40. Welsch CW: Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: A review and tribute to Charles Brenton Huggins. Cancer Res 45: 3415–3443, 1985

    PubMed  Google Scholar 

  41. Rudali G, Coezy E, Chemama R: Mammary carcinogenesis in female and male mice receiving contraceptives or gestagens. J Natl Cancer Inst 49: 813–819, 1972

    PubMed  Google Scholar 

  42. Society of Toxicologic Pathologists Second International Symposium. Design of Carcinogenicity studies: Considerations in Pathology Interpretation. Arlington, VA, 5: 9–11, 1983

    Google Scholar 

  43. Russo IH, Pokorzynski T, Russo J: Asynchronous development of the rat mammary glands: A determining factor in carcinogenesis. Breast Cancer Res Treat 8: 108, 1986

    Google Scholar 

  44. Russo J, Russo IH, van Zwieten MJ, Rogers AE, Gusterson B: Classification of neoplastic and non-neoplastic lesions of the rat mammary gland. In: Jones TC, Konishi Y, Mohr U (eds), Integument and Mammary Gland, Monograph series on the Pathology of Laboratory Animals. Springer-Verlag, Berlin, 1988 (In press)

    Google Scholar 

  45. Kleinbaum G, Kupper L: Applied Regression and Other Multivariable Methods. North Scituate, MA: Duxbury Press 1978, pp 362–366

    Google Scholar 

  46. Zar JH: Biostatistical Analysis. Second Edition. Prentice-Hall, Inc., Englewood Cliffs, NJ, 1984, pp 185–309

    Google Scholar 

  47. Fleiss JL: Statical Methods for Rates and Proportions. Second Edition. John Wiley and Sons, New York, NY, 1981, pp 64–67

    Google Scholar 

  48. Kledzik BS, Bradley CJ, Meites J: Reduction of carcinogen-induced mammary cancer incidence in rats by early treatment with hormones and drugs. Cancer Res 34: 2953–2956, 1974

    PubMed  Google Scholar 

  49. Huggins C, Moon R, Morii S: Extinction of experimental mammary cancer, I. Estradiol-17B and progesterone. Proc Natl Acad Sci 48: 379–386, 1962

    PubMed  Google Scholar 

  50. Weisburger JH, Weisburger EK, Griswold DP, Casey AE: Reduction of carcinogen-induced breast cancer in rats by an anti-fertility drug. Life Sci 7: 259–266, 1968

    PubMed  Google Scholar 

  51. McCarthy JD: Influence of two contraceptives on induction of mammary cancer in rats. Am J Surg 110: 720–723, 1965

    PubMed  Google Scholar 

  52. Schardein JL, Kaump DH, Woosley ET, Jellema MM: Long term toxicologic and tumorigenesis studies on an oral contraceptive agent in albino rats. Toxicol Applied Pharmacol 16: 10–23, 1970

    Google Scholar 

  53. Ochs H, Dusterberg B, Gunzel P, Schulte-Hermann R: Effect of tumor promoting contraceptive steroids on growth and drug metabolizing enzymes in rat liver. Cancer Res 46: 1224–1232, 1986

    PubMed  Google Scholar 

  54. King MM, McCay PB, Russo IH: Dietary fat may influence DMBA-initiated mammary gland carcinogenesis by modification of mammary gland development. In: Roe DA (ed) Diet, Nutrition and Cancer: from Basic Research to Policy Implications. Alan R. Liss, Inc., New York, 1983 pp 61–90

    Google Scholar 

  55. Hawrylewicz EJ, Huang HH, Kissane JQ, Drab EA: Enhancement of 7,12-dimethylbenzanthracene (DMBA) mammary tumorigenesis by high dietary protein in rats. Nutr Rep Int 26: 793–806, 1982

    Google Scholar 

  56. Calaf G, Russo IH, Roi LD, Russo J: Effects of peptides and steroid hormones on cell kinetic parameters of normal human breast tissue in organ culture. In Vitro Cell Develop Biol 22: 135–140, 1986

    Google Scholar 

  57. McManus MJ, Welsch CW: Hormone-induced ductal DNA synthesis of human breast tissues maintained in the athymic nude mice. Cancer Res 41: 3300–3305, 1981

    PubMed  Google Scholar 

  58. Lippman ME, Huff KK, Jakesz R, Hecht T, Kasid A, Bates S, Dickson RB: Estrogens regulate production of specific growth factors in hormone-dependent human breast cancer. In: Angeli A, Bradlow HL, Dogliotti L (eds) Endocrinology of the Breast: Basic and Clinical Aspects. Ann NY Acad Sci 464: 11–16, 1986

    PubMed  Google Scholar 

  59. Rochefort H, Capony F, Garcia M, Vignon F: The 52 K estrogen-regulated protein secreted by breast cancer cells and its clinical Potential. In: Angeli A, Bradlow HL, Dogliotti L (eds) Endocrinology of the Breast: Basic and Clinical Aspects. Ann NY Acad Sci 464: 190–201, 1986

    PubMed  Google Scholar 

  60. Welsch CW, Goodrich-Smith M, Brown CK, Roth L: The prophylaxis of rat and mouse mammary gland tumorigenesis by suppression of prolaction secretion: a reappraisal. Breast Cancer Res Treat 1: 225–232, 1981

    PubMed  Google Scholar 

  61. Minasian-Batmanian LC, Jabara AG: Hormone and drug effects on growth of DMBA mammary tumors and plasma prolactin levels in adreno-ovariectomized rats. Br J Cancer 43: 832–841, 1981

    PubMed  Google Scholar 

  62. Rose DP, Noonan JJ: Influence of prolactin and growth hormone on rat mammary tumors induced by N-nitroso-methylurea. Cancer Res 42: 35–38, 1982

    PubMed  Google Scholar 

  63. Meites J: Relation of prolactin and estrogen to mammary tumorigenesis in the rat. J Natl Cancer Inst 48: 1217–1224, 1972

    PubMed  Google Scholar 

  64. Nagasawa H, Yanai R: Changes in serum levels of prolactin shortly before and after parturition in rat. Endocrinol 19: 139–143, 1972

    Google Scholar 

  65. Nagasawa H, Yanai R, Taniguchi H: Importance of mammary gland DNA synthesis on carcinogen-induced mammary tumors in rats. Cancer Res 36: 2223–2226, 1976

    PubMed  Google Scholar 

  66. Nagasawa H, Morii S: Prophylaxis of spontaneous mammary tumorigenesis by temporal inhibition of prolactin secretion in rats at young ages. Cancer Res 41: 1935–1937, 1981

    PubMed  Google Scholar 

  67. Yanai R, Nagasawa H: Effects of pituitary graft and 2-bromo-ergocryptine on mammary DNA synthesis in mice in relation to tumorigenesis. J Natl Cancer Inst 56: 1055–1056, 1976

    PubMed  Google Scholar 

  68. Nagasawa H, Yanai R: Effects of prolactin or growth hormone on growth of carcinogen-induced mammary tumors of adreno-ovariectomized rats. Int J Cancer 6: 488–492, 1970

    PubMed  Google Scholar 

  69. Livolsi VA, Stadel BV, Kelsey JL, Holford TR, White C: Fibrocystic breast disease in oral contraceptive users. New Engl J Med 299: 381–385, 1978

    PubMed  Google Scholar 

  70. Pastides H, Kelsey JL, Livolsi VA, Holford TR, Fischer DB, Goldenberg IS: Oral contraceptive use and fibrocystic disease with special reference to its histopathology. J Natl Cancer Inst 71: 5–9, 1983

    PubMed  Google Scholar 

  71. Cole PT: Oral contraceptives and breast neoplasia. Cancer 39: 1906–1918, 1977

    PubMed  Google Scholar 

  72. Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. Oral contraceptive use and the risk of breast cancer. N Engl J Med 315: 405–411, 1986

    Google Scholar 

  73. Wang DY, Fentiman IS: Epidemiology and endocrinology of benign breast disease. Breast Cancer Res Treat 6: 5–36, 1985

    PubMed  Google Scholar 

  74. McCann J: Oral contraceptive use shows no effect on breast cancer outcome. Oncol Times, VII, 5: 35, 1985

    Google Scholar 

  75. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer, cervical cancer and depot medroxyprogesterone acetate. Lancet II, 1207–1208, 1984

    Google Scholar 

  76. Vessey MP, Doll R, Jones K, McPherson K, Yeates D: An epidemiological study of oral contraceptives and breast cancer. Br Med J 1: 1757–1760, 1979

    PubMed  Google Scholar 

  77. Thomas DB: Role of exogenous female hormones in altering the risk of benign and malignant neoplasms in humans. Cancer Res 38: 3991–4000, 1978

    PubMed  Google Scholar 

  78. Rosner D, Lane WW: Oral contraceptive use has no adverse effect on the prognosis of breast cancer. Cancer 57: 591–596, 1986

    PubMed  Google Scholar 

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Russo, I.H., Frederick, J. & Russo, J. Hormone prevention of mammary carcinogenesis by norethynodrel-mestranol. Breast Cancer Res Tr 14, 43–56 (1989). https://doi.org/10.1007/BF01805975

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