Breast Cancer Research and Treatment

, Volume 72, Issue 2, pp 153–162 | Cite as

The Effect of Flutamide and Tamoxifen on Sex Hormone-Induced Mammary Carcinogenesis and Pituitary Adenoma

  • G. Leung
  • S.W. Tsao
  • Y.C. Wong


We have established a female Noble rat model to explore the mechanisms of hormonal mammary carcinogenesis. Based on the previous finding that the dose of testosterone affects only the latency period of mammary cancer, not the final incidence and that androgen upregulates apoptotic activity in pre-malignant mammary glands, we hypothesised that estrogen is the initiator and androgen the promoter for hormonal mammary carcinogenesis of the rats. In the present study, rats were treated with the sex hormones together with flutamide and tamoxifen for both short term (7 and 13 weeks) and long term (12 months) durations. We showed that tamoxifen could totally inhibit mammary carcinogenesis while flutamide cause a delay and reduction in tumour incidence in the 12 months treatment term. Blocking effect of flutamide and tamoxifen on T + E2 (testosterone and 17β-estradiol) short-terms treatment was demonstrated by the similar histological changes identified in the mammary glands of the T + E2 and drug treated rats to that of the age matched E2 and T controls, respectively. These findings give further support for the role of estrogen and androgen in mammary carcinogenesis. Autopsy of the tumour bearing rats showed presence of pituitary macroadenoma causing compression and atrophy of the brain stem. Immunohistochemical staining of these adenomas showed a predominance of prolactin-secreting cells. Serum assay also showed a corre-sponding increase in circulatory prolactin level. Tamoxifen was also effective in blocking the formation of pituitary adenoma in the sex hormone treated rats. Pituitary size and level of prolactin were higher in the T + E2 +flutamide group than the T + E2 group in both short-term and long-term treatments. It suggests that testosterone may have a role in counteracting estradiol stimulation on the pituitary lactotropes although it is synergistic to estrogen in mammary carcinogenesis. Pituitary adenomas were found in all rats that developed mammary adenocarcinoma but not vice versa suggesting that prolactin level elevation alone cannot lead to mammary tumorigenesis. The animal model, in addition to mammary carcinogenesis, may be useful for investigation of anti-estrogen therapy in pituitary adenomas.

flutamide mammary carcinogenesis pituitary adenoma sex hormones tamoxifen 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Landis SH, Murray T, Bolden S, Wingo PA: Cancer statistics, 1999. Ca: A Cancer Clinicians 49: 8–31, 1999Google Scholar
  2. 2.
    Krieger N: Exposure, susceptibility, and breast cancer risk: a hypothesis regarding exogenous carcinogens, breast tissue development, and social gradients, including black/white differences, in breast cancer incidence. Breast Cancer Res Treat13: 205–223, 1989Google Scholar
  3. 3.
    Brinton LA, Schairer C, Hoover RN, Fraumeni Jr JF: Menstrual factors and risk of breast cancer. Cancer Invest 6: 245–254, 1988Google Scholar
  4. 4.
    Dorgan JF, Longcope C, Stephenson Jr HE, Falk RT, Miller R, Franz C, Kahle L, Campbell WS, Tangrea JA, Schatzkin A: Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk. Cancer Epidem Biomar 5: 533–539, 1996Google Scholar
  5. 5.
    Hansen RK, Fuqua SAW: Estrogen receptor and breast cancer. In: Bowcock AM (ed) Breast Cancer. Molecular Genetics, Pathogenesis, and Therapeutics. 1999.Google Scholar
  6. 6.
    Dorgan JF, Longcope C, Stephenson Jr HE, Falk RT, Miller R, Franz C, Kahle L, Campbell WS, Tangrea JA, Schatzkin A: Serum sex hormone levels are related to breast cancer risk in postmenopausal women. Environ Health Persp 105 (suppl 3) 583–585, 1997Google Scholar
  7. 7.
    Cauley JA, Lucas FL, Kuller LH, Stone K, Browner W, Cummings SR: Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer. Study of osteoporotic fractures research group. Ann Int Med 130: 270–277, 1999Google Scholar
  8. 8.
    Veronesi U, Pizzocaro G: Breast cancer in women subsequent to cystic disease of the breast. Surgery Gynec Obst 126: 529–532, 1968Google Scholar
  9. 9.
    Gratterola R: Anovulation and increased androgenic activity as breast cancer risk in women with fibrocystic disease of the breast. Cancer Res 38: 3051–3054, 1978Google Scholar
  10. 10.
    Secreto G, Toniolo P, Berrino F, Recchione C, Di Pietro S, Fariselli G, Decarli A: Increased androgenic activity and breast cancer risk in premenopausal women. Cancer Res 44: 5902–5905, 1984Google Scholar
  11. 11.
    Ruizeveld de Winter JA, Trapman J, Vermey M, Mulder E, Zegers ND, van der Kwast TH: Androgen receptor expression in human tissues: an immunohistochemical study. J Histo Cytochem 39: 927–936, 1991Google Scholar
  12. 12.
    Bryan RM, Mercer RJ, Bennett RC, Rennie GC, Lie TH, Morgan FJ: Androgen receptors in breast cancer. Cancer 54: 2436–2440, 1984Google Scholar
  13. 13.
    Noble RL: A new characteristic transplantable type of breast carcinoma in Nb rats following combined estrogen–androgen treatment. Proc Am Assoc Cancer Res 17: 221, 1976Google Scholar
  14. 14.
    Xie B, Tsao SW, Wong YC: Sex hormone-induced mammary carcinogenesis in female noble rats: the role of androgens. Carcinogenesis 20: 1597–1606, 1999Google Scholar
  15. 15.
    Liao DZ, Hou X, Pantazis CG, Bai S, Li SA, Li JJ: Combined treatment of estrogen and androgen is more effective than estrogen alone in induction of mammary adenocarcinoma in the male Noble rat. Proc Am Assoc Cancer Res 39: 387, 1998Google Scholar
  16. 16.
    Liao DZ, Pantazis CG, Hou X, Li SA: Promotion of estrogeninduced mammary gland carcinogenesis by androgen in the male Noble rat: probable mediation by steroid receptors. Carcinogenesis 19: 2173–2180, 1998Google Scholar
  17. 17.
    Xie B, Tsao SW, Wong YC: Induction of high incidence of mammary tumour in female Noble rats with a combination of 17beta-oestradiol and testosterone. Carcinogenesis 20: 1069–1078, 1999Google Scholar
  18. 18.
    Xie B, Tsao SW, Wong YC: Sex hormone-induced mammary carcinogenesis in the female Noble rats: expression of bcl-2 and bax in hormonal mammary carcinogenesis. Breast Cancer Res Treat 61: 45–57, 2000Google Scholar
  19. 19.
    Rosen PP: Rosen's Breast Pathology. Lippincott–Raven, New York, 1997Google Scholar
  20. 20.
    Ashley DJB: Evans' Histological Appearances of Tumours. Churchill Livingstone, Edinburgh, 1990Google Scholar
  21. 21.
    Goldspiel BR, Kohler DR: Flutamide: an antiandrogen for advanced prostate cancer. DICP 24: 616–623, 1990Google Scholar
  22. 22.
    Peets EA, Henson MF, Neri R: On the mechanism of the antiandrogenic action of flutamide (alpha-alpha-alpha-trifluoro-2-methyl-4_-nitro-m-propionotoluidide) in the rat. Endocrinology 94: 532–540, 1974Google Scholar
  23. 23.
    Raghow S, Kuliyev E, Steakley M, Greenberg N, Steiner MS: Efficacious chemoprevention of primary prostate cancer by flutamide in an autochthonous transgenic model. Cancer Res 60: 4093–4097, 2000Google Scholar
  24. 24.
    Xie B, Tsao SW, Wong YC: Sex hormone-induced mammary carcinogenesis in female Noble rats: expression of TGFbeta1 and its receptors, TGF-alpha, and EGF-R in mammary carcinogenesis. Breast Cancer Res Treat 58: 227–239, 1999Google Scholar
  25. 25.
    Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE: Increased cell division as a cause of human cancer. Cancer Res 50: 7415–7421, 1990Google Scholar
  26. 26.
    Durnberger H, Heuberger B, Schwartz P, Wasner G, Kratochwil K: Mesenchyme-mediated effect of testosterone on embryonic mammary epithelium. Cancer Res 38: 4066– 4070, 1978Google Scholar
  27. 27.
    Schreihofer DA, Stoler MH, Shupnik MA: Differential expression and regulation of estrogen receptors (ERs) in rat pituitary and cell lines: estrogen decreases ERalpha protein and estrogen responsiveness. Endocrinology 141: 2174–2184, 2000Google Scholar
  28. 28.
    Friend KE, Chiou YK, Lopes MB, Laws Jr ER, Hughes KM, Shupnik MA: Estrogen receptor expression in human pituitary: correlation with immunohistochemistry in normal tissue, and immunohistochemistry and morphology in macroadenomas. J Clin Endocr Metab 78: 1497–1504, 1994Google Scholar
  29. 29.
    Nishihara E, Nagayama Y, Inoue S, Hiroi H, Muramatsu M, Yamashita S, Koji T: Ontogenetic changes in the expression of estrogen receptor alpha and beta in rat pituitary gland detected by immunohistochemistry. Endocrinology 41: 615–620, 2000Google Scholar
  30. 30.
    Shull JD, Spady TJ, Snyder MC, Johansson SL, Pennington, KL: Ovary-intact, but not ovariectomized female ACI rats treated with 17beta-estradiol rapidly develop mammary carcinoma. Carcinogenesis 18: 1595–1601, 1997Google Scholar
  31. 31.
    Spady TJ, Harvell DM, Snyder MC, Pennington KL, Mc-Comb RD, Shull JD: Estrogen-induced tumorigenesis in the Copenhagen rat: disparate susceptibilities to development of prolactin-producing pituitary tumors and mammary carcinomas. Cancer Lett 124: 95–103, 1998Google Scholar
  32. 32.
    Shull JD, Birt DF, McComb RD, Spady TJ, Pennington KL, Shaw-Bruha CM: Estrogen induction of prolactin-producing pituitary tumors in the Fischer 344 rat: modulation by dietaryenergy but not protein consumption. Mol Carcinogen 23: 96–105, 1998Google Scholar
  33. 33.
    Kovacs K, Stefaneanu L, Ezzat S, Smyth HS: Prolactinproducing pituitary adenoma in a male-to-female transsexual patient with protracted estrogen administration. A morphologic study. Arch Pathol Lab Med 118: 562–565, 1994Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • G. Leung
    • 1
  • S.W. Tsao
    • 1
  • Y.C. Wong
    • 1
  1. 1.Department of Anatomy, Faculty of MedicineUniversity of Hong KongHong KongChina

Personalised recommendations