Role of Hormones in Mammary Cancer Initiation and Progression

  • Irma H. Russo
  • Jose Russo


Breast cancer, the most frequent spontaneousmalignancy diagnosed in women in the Western world, isa classical model of hormone dependent malignancy. Thereis substantial evidence that breast cancer risk is associated with prolonged exposure to femalehormones, since early onset of menarche, late menopause,hormone replacement therapy and postmenopausal obesityare associated with greater cancer incidence. Among these hormonal influences a leading roleis attributed to estrogens, either of ovarian orextra-ovarian origin, as supported by the observationsthat breast cancer does not develop in the absence of ovaries, ovariectomy causes regression ofestablished malignancies, and in experimental animalmodels estrogens can induce mammary cancer. Estrogensinduce in rodents a low incidence of mammary tumors after a long latency period, and only in thepresence of an intact pituitary axis, with induction ofpituitary hyperplasia or adenomas andhyperprolactinemia. Chemicals, radiation, viruses andgenomic alterations have all been demonstrated to have a greatertumorigenic potential in rodents. Chemical carcinogensare used to generate the most widely studied rat models;in these models hormones act as promoters or inhibitors of the neoplastic process. Theincidence and type of tumors elicited, however, arestrongly influenced by host factors. The tumorigenicresponse is maximal when the carcinogen is administered to young and virgin intact animals in which themammary gland is undifferentiated and highlyproliferating. The atrophic mammary gland ofhormonally-deprived ovariectomized or hypophysectomizedanimals does not respond to the carcinogenic stimulus.Administration of carcinogen to pregnant, parous orhormonally treated virgin rats, on the other hand, failsto elicit a tumorigenic response, a phenomenon attributed to the higher degree ofdifferentiation of the mammary gland induced by thehormonal stimulation of pregnancy. In women a majorityof breast cancers that are initially hormone dependentare manifested during the postmenopausal period. Estradiolplays a crucial role in their development and evolution.However, it is still unclear whether estrogens arecarcinogenic to the human breast. The apparentcarcinogenicity of estrogens is attributed to receptor-mediatedstimulation of cellular proliferation. Increasedproliferation could result in turn in accumulation ofgenetic damage and stimulation of the synthesis of growth factors that act on the mammaryepithelial cells via an autocrine or paracrine loop.Alternatively estrogens may induce cell proliferationthrough negative feedback by removing the effect of one or several inhibitory factors present in theserum. Multidisciplinary studies are required for theelucidation of the mechanisms responsible for theinitiation of breast cancer. Understanding of suchmechanisms is indispensable for developing a rationalbasis for its prevention and control.



Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. P. Cunningham (1997). Giving life to numbers. CA Cancer J. Clin. 47:3-4.Google Scholar
  2. 2.
    S. L. Parker, T. Tong, S. Bolden, and P. A. Wingo (1997). Cancer statistics, 1997. CA Cancer J. Clin. 47:5-27.Google Scholar
  3. 3.
    S. E. King and D. Schottenfeld (1996). The epidemic of breast cancer in the U. S. — Determining the factors. Oncology 10:453-462.Google Scholar
  4. 4.
    L. A. Gaudette, C. Silberberg, C. A. Altmayer, and R. N. Gao (1996). Trends in breast cancer incidence and mortality. Health Reports. 8:29-40.Google Scholar
  5. 5.
    A. Seow, S. S. Duffy, M. A. McGee, J. Lee, and H. P. Lee (1996). Breast cancer in Singapore: Trends in incidence 1968-1992. Int. J. Epidemiol. 25,40-45.Google Scholar
  6. 6.
    G. T. Beatson (1896). On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment, with illustrative cases. Lancet 2:104-107.Google Scholar
  7. 7.
    C. Huggins (1965). Two principles in endocrine therapy of cancers: Hormone deprival and hormone interference. Cancer Res. 25:1163-1167.Google Scholar
  8. 8.
    D. F. Easton, D. T. Bishop, D. Ford, and G. P. Crockford (1993). The breast cancer linkage consortium. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am. J. Hum. Genet. 52:678-701.Google Scholar
  9. 9.
    I. H. Russo and J. Russo (1996). Mammary gland neoplasia in long term rodent studies. Environ. Health Perspect. 104:938-967.Google Scholar
  10. 10.
    J. L. Kelsey and P. L. Horn-Ross (1993). Breast cancer: Magnitude of the problem and descriptive epidemiology. Epidemiol. Rev. 15:7-16.Google Scholar
  11. 11.
    E. Petrodidou, E. Syrigou, N. Toupadaki, X. Zavitsanos, and W. Willett (1996). Determinants of age at menarche as early life predictors of breast cancer risk. Int. J. Cancer 68:193-198.Google Scholar
  12. 12.
    M. Lambe, C.-C. Hsieh, H.-W. Chan, A. Ekbom, D. Trichopoulos, and H. O. Adami (1996). Parity, age at first and last birth, and risk of breast cancer: A population-based study in Sweden. Breast Cancer Res. Treat. 38:305-311.Google Scholar
  13. 13.
    S. L. Hancock, M. A. Tucker, and R. T. Hoppe (1993). Breast cancer after treatment of Hodgkin' s disease. J. Natl. Cancer Inst. 85:25-31.Google Scholar
  14. 14.
    J. Russo and I. H. Russo (1994). Toward a physiological approach to breast cancer prevention. Cancer Epidemiol. Biomarkers Prev. 3:353-364.Google Scholar
  15. 15.
    S. Nandi, R. C. Guzman, and J. Yang (1995). Hormones and mammary carcinogenesis in mice, rats, and humans: A unifying hypothesis. Proc. Natl. Acad. Sci. USA 92:3650-3657.Google Scholar
  16. 16.
    J. Russo and I. H. Russo (1987). Biological and molecular bases of mammary carcinogenesis. Lab Invest. 57:112-137.Google Scholar
  17. 17.
    J. Russo, B. A. Gusterson, A. E. Rogers, I. H. Russo, S. R Wellings, and M. J. Van Zwieten (1990). Comparative study of human and rat mammary tumorigenesis. Lab. Invest. 62:1-32.Google Scholar
  18. 18.
    D. L. McCormick, C. B. Adamowski, A. Fiks, R. C. Moon (1981). Lifetime dose-response relationships for mammary tumor reduction by a single administration of N-methyl-Nnitrosurea. Cancer Res. 41:1690-1694.Google Scholar
  19. 19.
    C. J. Grubbs, D. R. Farnell, D. L. Hill, and K. C. McDonough (1985). Chemopreventio n of N-nitroso-N-methylurea-induced mammary cancers by pretreatment with 17 beta-estradiol and progesterone. J. Natl. Cancer Inst. 74:927-931.Google Scholar
  20. 20.
    W. P. Bocchinfuso and K. S. Korach (1997). Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J. Mam. Gland Biol. Neoplasia 2:323-334.Google Scholar
  21. 21.
    R. C. Humphreys, J. Lydon, B. W. O' Malley, and J. M. Rosen (1997). Use of PRKO mice to study the role of progesterone in mammary gland development. J. Mam. Gland Biol. Neoplasia 2:343-353.Google Scholar
  22. 22.
    D. K. Sinha, J. E. Pazik, and T. L. Dao (1983). Progression of rat mammary development with age and its relationship to carcinogenesis by a chemical carcinogen. Int. J. Cancer 31:321-327.Google Scholar
  23. 23.
    J. R. Curtis (1982). The role of 7, 12 DMBA and three hormones in 7, 12 DMBA-induced rat mammary cancer: three hypotheses. Med. Hypoth. 9:489-507.Google Scholar
  24. 24.
    G. R. Cunha, P. Young, Y. K. Hom, P. S. Cooke, J. A. Taylor, and D. B. Lubahn (1997). Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombination experiments. J. Mam. Gland Biol. Neoplasia 2:393-401.Google Scholar
  25. 25.
    R. G. Edwards, C. M. Howles, and C. Macnamee (1990). Clinical endocrinology of reproduction. In E.-E Baulieu and P. A. Kelly (eds.), Hormones: From Molecules to Disease Chapman and Hall, New York and London, pp. 457-476.Google Scholar
  26. 26.
    R. B. Dickson, M. Bano, M. D. Johnson, Y. E. Shi, I. Martinez-Lacaci, L. T. Amundadottir, B. Ziff, and J. Kurebayashi (1994). Steroid regulation of growth factors and protooncogenes in the normal and malignant mammary gland. In S. A. Khan and G. M. Stancel (eds.), Protooncogenes and Growth Factors in Steroid Hormone Induced Growth and Differentiation, CRC Press, Boca Raton, Florida, pp. 143-74.Google Scholar
  27. 27.
    B. K. Vonderhaar (1988). Regulation of development of the normal mammary gland by hormones and growth factors. In M. E. Lippman and R. B. Dickson (eds.), Breast Cancer: Cellular and Molecular Biology, Kluwer, Boston, pp. 251-294.Google Scholar
  28. 28.
    I. H. Russo, J. Medado, and J. Russo (1989). Endocrine Influ-ences on Mammary Structure and Development. In T. C. Jones, U. Mohr, and R. D. Hunt (eds.), Integument and Mammary Gland of Laboratory Animals, Springer Verlag, Berlin, pp. 252-266.Google Scholar
  29. 29.
    J. J. Peluso (1992). Morphologic and physiologic features of the ovary. In U. Mohr, D. L. Dungworth, and C. C. Capen (eds.), Pathobiology of the Aging Rat, ILSI Press, Washington, D.C., pp. 337-349.Google Scholar
  30. 30.
    S. Y. Yung (1988). Inhibins, activins and follistatins: Gonadal proteins modulating the secretion of follicle-stimulating hormone. Endocrine Rev. 9:267-293.Google Scholar
  31. 31.
    P. A. Kelly, B. I. Posner, T. Tsushima, and H. G. Friessen (1974). Studies of insulin, growth hormone and PRL binding: Ontogenesis, effects of sex and pregnancy Endocrinology 95:532-539Google Scholar
  32. 32.
    F. Labrie (1990). Glycoprotein hormones: Gonadotropins and thyrotropin. In E.-E Baulieu, and P. A. Kelly (eds.), Hormones: From Molecules to Disease, Chapman and Hall, New York and London, pp. 257-275.Google Scholar
  33. 33.
    T. K. Woodruff and K. E. Mayo (1990). Regulation of inhibin synthesis in the rat ovary. Ann. Rev. Physiol. 52:807-827.Google Scholar
  34. 34.
    D. T. Lincoln, F. Sinowatz, E. el-Hifnawi, R. L. Hughes, and M. Waters (1995). Evidence of a direct role for growth hormone (GH) in mammary gland proliferation and lactation. Anatomia, Histologia, Embryologia 24:107-115Google Scholar
  35. 35.
    J. Russo, Y. F. Hu, X. Ao, C. Grill, and I. H. Russo (1997). Critical appraisal of estrogens as carcinogenic agents in the human breast. Menopause Rev.(submitted).Google Scholar
  36. 36.
    M. M. King, P. McCoy, and I. H. Russo (1983). Dietary fat may influence DMBA-initiated mammary gland carcinogenesis by modification of mammary gland development. In D. A. Roe (ed.), Current Topics in Nutrition and Disease, Alan R. Liss, Inc. pp. 61-90.Google Scholar
  37. 37.
    J. Russo, L. K. Tay, and I. H. Russo (1982). Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res. Treat. 2:5-37.Google Scholar
  38. 38.
    G. Leclercq and J. C. Heuson (1979). Physiological and phar-macological effects of estrogens in breast cancer. Biochem. Biophys. Acta 560:427-455.Google Scholar
  39. 39.
    A. G. Jabara and A. G. Harcourt (1971). Effect of progesterone, ovariectomy and adrenalectomy on mammary tumors induced by 7,12-dimethylb enzathracene in Sprague-Dawley rats. Pathology 3:209-214.Google Scholar
  40. 40.
    A. Manni, J. E. Trujillo, and O. H. Pearson (1977). Predominant role of prolactin in stimulating the growth of 7,12-dimethylbe n-za(a)anthracene-induced rat mammary tumors. Cancer Res. 37:1216-1219.Google Scholar
  41. 41.
    C. W. Welsch (1978). Prolactin and the development and progression of early neoplastic mammary gland lesions. Cancer Res. 38:4054-4058.Google Scholar
  42. 42.
    C. W. Welsch, C. K. Brown, and M. Goodrich-Smith (1979). Inhibition of mammary tumorigenesis in carcinogen-treat ed Lewis rats by suppression of prolactin secretion. J. Natl. Cancer Inst. 63:1211-1214.Google Scholar
  43. 43.
    R. Das and B. K. Vonderhaar (1997). Prolactin as a mitogen in mammary cells. J. Mam. Gland Biol. Neoplasia 2:29-39.Google Scholar
  44. 44.
    A. E. Wakeling (1996). Physiological effects of pure antiestro-gens. In J. R. Pasqualini and B. Katzenellenbogen (eds.), Hor-mone-Dependent Cancer, Marcel Dekker, Inc., New York, pp. 107-118.Google Scholar
  45. 45.
    R. C. Moon, G. J. Kelloff, C. J. Detrisac, V. E. Steele, C. F. Thomas, and C. C. Sigman (1992). Chemopreventio n of MNU-induced mammary tumors in the mature rat by 4-HPR and tamoxifen. Anticancer Res. 12:1147-1153.Google Scholar
  46. 46.
    D. L. McCormick and R. C. Moon (1986). Retinoid-tamoxifen interaction in mammary cancer chemoprevention. Carcinogenesis 7:193-196.Google Scholar
  47. 47.
    R. L. Stouffer (1990). Corpus luteum function and dysfunction. Clin. Obstet. Gynecol. 33:668-689.Google Scholar
  48. 48.
    C. K. W. Watts, N. R. C. Wilcken, J. A. Hamilton, K. J. E. Sweeney, A. Musgrove, and R. L. Sutherland (1996). Mecha-nisms of antiestrogen, progestin/antip rogestin, and retinoid inhibition of cell cycle progression in breast cancer cells. In J. R. Pasqualini and B. Katzenellenboge n (eds.), Hormone-Dependent Cancer, Marcel Dekker, Inc., New York, pp. 119-140.Google Scholar
  49. 49.
    I. H. Russo, P. Gimotty, M. Dupuis, and J. Russo (1989). Effect of the progestagen medroxyprogeste rone acetate on mammary carcinogenesis. Brit. J. Cancer 59:210-216.Google Scholar
  50. 50.
    C. M. Aldaz, Q. Y. Liao, A. Paladugu, S. Rhem, and H. Wang (1996). Allelotypic and cytogenetic characterization of chemi-cally induced mouse mammary tumors: high frequency of chro-mosome 4 loss of heterozygosity at advanced stages of progression. Mol. Carcinog. 17:126-133.Google Scholar
  51. 51.
    Y. Lino, T. Ogawa, M. Yoshida, H. Ishikawa, M. Izuo, and H. Takikawa (1990). Effects of sequential and combined endocrine therapies on the growth of 7,12-dimethylbe nz [alpha] anthra-cene-induced rat mammary carcinoma. Jap. J. Clin. Oncol. 20:259-262.Google Scholar
  52. 52.
    R. D. Wiehle and J. L. Wittliff (1983). Alterations in sex-steroid hormone receptors during mammary gland differentiation in the rat. Comp. Biochem. Physiol. 76:409-417.Google Scholar
  53. 53.
    G. A. Jahn, M. Edery L. Belair, P. A. Kelly, and J. Dijiane (1991). PRL receptor gene expression in rat mammary gland and liver during pregnancy and lactation. Endocrinology 128:2976-2984.Google Scholar
  54. 54.
    C. J. Grubbs, M. M. Juliana, D. L. Hill, L. M. Whitaker (1986). Suppression by pregnancy of chemically induced preneoplastic cells of the rat mammary gland. Anticancer Res. 6:2395-2401.Google Scholar
  55. 55.
    D. R. Ciocca, A. Parente and J. Russo (1982). Endocrinologic milieu and susceptibility of the rat mammary gland to carcino-genesis. Am. J. Pathol. 109:47-56.Google Scholar
  56. 56.
    I. H. Russo, M. Koszalka, and J. Russo (1991). Comparative study of the influence of pregnancy and hormonal treatment on mammary carcinogenesis. Brit. J. Cancer 64:481-484.Google Scholar
  57. 57.
    I. H. Russo, M. Koszalka, and J. Russo (1990). Protective effect of chorionic gonadotropin on DMBA-induced mammary carcinogenesis. Brit. J. Cancer 62:243-247.Google Scholar
  58. 58.
    D. L. McCormick, K. V. Rao, W. D. Johnson, T. A. Bowman-Gram, V. E. Steele, R. A. Lubet, and G. J. Kellof (1996). Exceptional chemopreventive activity of low dose dehydroepi-androsterone in the rat mammary gland. Cancer Res. 56:1724-1726.Google Scholar
  59. 59.
    H. Ishikawa, Y. Lino, M. Izuo, and H. Takikawa (1986). Com-bined therapies with medroxyprogester one acetate (MPA) in DMBA-induced rat mammary cancer. Gan No Rinsho— Japanese J. Cancer Clinics 32:151-155.Google Scholar
  60. 60.
    J. Russo and I. H. Russo (1997). Role of Differentiation in the pathogenesis and prevention of breast cancer. Endocrine Related Cancer 4:7-21.Google Scholar
  61. 61.
    A. M. Soto and C. Sonnenschein (1987). Cell proliferation of estrogen-sensiti ve cells: the case for negative control. Endomonecrine Rev. 48:52-58.Google Scholar
  62. 62.
    K. K. Huff, C. Knabbe, R. Lindsey, D. Kaufman, D. Bronzert, M. E. Lippman, and R. B. Dickson (1988). Multihormonal regulation of insulin-like growth factor-1-related protein in MCF-7 human breast cancer cells. Mol. Endocrinol. 2:200-208.Google Scholar
  63. 63.
    B. S. Katzenellenboge n, K. L. Kendra, M. J. Norman, and Y. Berthois (1987). Proliferation, hormonal responsiveness and estrogen receptor content of MCF-7 human breast cancer cells growth in the short-term and long-term absence of estrogens. Cancer Res. 47:4355-4360.Google Scholar
  64. 64.
    J. Gerdes, U. Schwab, H. Lemke and H. Stein (1983). Production of mouse-monoclon al antibody reactive with a human nuclear antigen associated with cell proliferation. Int. J. Cancer 31:13-20.Google Scholar
  65. 65.
    G. Calaf, M. E. Alvarado, G. E Bonney, K. K. Amfoh, and J. Russo (1995). Influence of lobular development on breast epithelial cell proliferation and steroid hormone receptor content. Int. J. Oncol. 7:1285-1288.Google Scholar
  66. 66.
    E. Anderson, R. B. Clarke, and A. Howell (1998). Estrogen responsiveness and control of normal human breast development. J. Mam. Gland Biology Neoplasia 3:23-35.Google Scholar

Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Irma H. Russo
  • Jose Russo

There are no affiliations available

Personalised recommendations