Skip to main content
SpringerLink
Log in

Inhibitory effect of a steroidal antiestrogen (EM-170) on estrone-stimulated growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat

  • Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

Recently, compounds having pure antiestrogenic activity have become available. In this study, we examined the activity of the new steroidal antiestrogen EM-170 (N-n-butyl, N-methyl-11-(16′α-chloro-3′,17′α-dihydroxy-estra-1′,3′,5′-(10′)-trien-7′α-yl) undecanamide) on the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma stimulated by treatment with estrone (E1), a steroid known to play an important role as precursor of 17β-estradiol (E2), especially in postmenopausal women. Twenty-five days after ovariectomy (OVX), tumor volume in control OVX animals decreased to 51.4 ± 11% of the initial volume; treatment with E1, administered by Silastic implants, stimulated tumor growth to 179 ± 21%. Treatment with the antiestrogen EM-170 at a dose of 200 µg (twice daily) not only completely reversed the stimulatory effect of E1, but also inhibited tumor growth to 30.5 ± 9.6%, an effect that is 41% (P < 0.01 vs OVX control) greater than that of ovariectomy alone. At a relatively low dose of 40 µg (twice daily), 20 days of treatment with EM-170 reversed by 55% the stimulatory effect of E1 (1.0 µg, subcutaneously, twice daily) on tumor growth in OVX animals. On the other hand, the antiestrogen also induced a significant inhibitory effect on 17β-hydroxysteroid dehydrogenase (17β-HSD) activity in the DMBA-induced mammary tumors, an effect that is in agreement with the marked reduction caused by the same treatment on tumor estradiol (E2) levels in E1-treated OVX animals. The present data show that the new steroidal antiestrogen EM-170 exerts a potent inhibitory effectin vivo on E1-stimulated growth of DMBA-induced mammary tumors, an effect that is probably mediated by both its antiestrogenic activity at the receptor level and its inhibitory effect on 17β-HSD, thus inhibiting local E2 formation and facilitating the action of the antiestrogen at the receptor level.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Huggins C, Grand LC, Brillantes FP: Mammary cancer induced by a single feeding of polynuclear hydrocarbons, and its suppression. Nature 189: 204–207, 1961

    Google Scholar 

  2. Asselin J, Labrie F, Kelly PA, Philibert D, Raynaud JP: Specific progesterone receptors in dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. Steroids 27: 395–404, 1976

    Google Scholar 

  3. Labrie F, Kelly PA, Asselin J, Raynaud JP: Potent inhibitory activity of a new antiestrogen, RU16117, on the development and growth of DMBA-induced rat mammary adenocarcinoma. In: Band G, Israel L (eds) Breast Cancer, A Multidisciplinary Approach. Recent Results in Cancer Research. Springer-Verlag, New York, vol 57, 1976, pp 109–120

    Google Scholar 

  4. Asselin J, Labrie F: Effects of estradiol and prolactin on steroid receptor levels in 7,12-dimethylbenz(a)anthracene-induced mammary tumors and uterus in the rat. J Steroid Biochem 9: 1079–1082, 1977

    Google Scholar 

  5. Spinola PG, Marchetti B, Labrie F: Adrenal steroids stimulate growth and progesterone receptor levels in rat uterus and DMBA-induced mammary tumors. Breast Cancer Res Treat 8: 241–248, 1986

    Google Scholar 

  6. Dickson RB, Lippman ME: Estrogenic regulation of growth and polypeptide growth factor secretion in human breast carcinoma. Endocr Rev 8: 29–43, 1987

    Google Scholar 

  7. Dowsett M, Goss PE, Powles TJ, Hutchinson G, Brodie AMH, Jeffcoate SL, Coombes RC: Use of the aromatase inhibitor 4-hydroxyandrostenedione in post-menopausal breast cancer: optimization of therapeutic doses and route. Cancer Res 47: 1957–1961, 1987

    Google Scholar 

  8. Miller WR: Fundamental research leading to improved endocrine therapy for breast cancer. J Steroid Biochem 27: 477–485, 1987

    Google Scholar 

  9. Furr BJ, Jordan VC: The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25: 127–205, 1984

    Google Scholar 

  10. McNab MW, Tallarida RJ, Joseph R: An evaluation of tamoxifen as a partial agonist by classical receptor theory, an explanation of the dual action of tamoxifen. Eur J Pharmacol 103: 321–326, 1984

    Google Scholar 

  11. Poulin R, Mérand Y, Poirier D, Lévesque C, Dufour JM, Labrie F: Antiestrogenic properties of keoxifene, trans-4-hydroxytamoxifen and ICI164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells. Breast Cancer Res Treat 14: 65–76, 1989

    Google Scholar 

  12. Bucourt R, Vignau M, Torelli V, Richard-Foy H, Geynet C, Secco-Milet C, Redeuil HG, Baulieu EE: New biospecific absorbents for the purification of estradiol receptor. J Biol Chem 253: 8221–8228, 1978

    Google Scholar 

  13. Wakeling AE, Bowler J: Steroidal pure antiestrogens. J Endocrinol 112: R7-R10, 1987

    Google Scholar 

  14. Dauvois S, Geng CS, Lévesque C, Mérand Y, Labrie F: Additive inhibitory effects of an androgen and the antiestrogen EM-170 on estradiol-stimulated growth of ZR-75-1 breast tumors in athymic mice. Cancer Res 51: 3131–3135, 1991

    Google Scholar 

  15. de Launoit Y, Dauvois S, Dufour M, Simard J, Labrie F: Inhibition of cell cycle kinetics and proliferation by the androgen 5α-dihydrotestosterone and antiestrogen N-n-butyl-N-methyl-11-(16′α-chloro-3′,17β-dihydroxy-estra-1′,3′,5′-(10′)-triene-7′α-yl) undecanamide in human breast cancer ZR-75-1 cells. Cancer Res 51: 2797–2802, 1991

    Google Scholar 

  16. Lévesque C, Mérand Y, Dufour JM, Labrie C, Labrie F: Synthesis and biological activity of new halo-steroidal antiestrogens. J Med Chem 34: 1624–1630, 1991

    Google Scholar 

  17. Labrie C, Martel C, Dufour JM, Lévesque C, Mérand Y, Labrie F: Novel compounds inhibit estrogen formation and action. Cancer Res 52: 610–615, 1992

    Google Scholar 

  18. Dauvois S, Labrie F: Androstenedione and androst-5-ene-3β,17β-diol stimulate DMBA-induced rat mammary tumors- role of aromatase. Breast Cancer Res Treat 13: 61–69, 1989

    Google Scholar 

  19. Dauvois S, Li S, Martel C, Labrie F: Inhibitory effect of androgens on DMBA-induced mammary carcinoma in the rat. Breast Cancer Res Treat 14: 299–306, 1989

    Google Scholar 

  20. Dauvois S, Spinola PG, Labrie F: Additive inhibitory effects of bromocriptine (CB-154) and medroxyprogesterone acetate (MPA) on dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat. Eur J Cancer Clin Oncol 25: 891–897, 1989

    Google Scholar 

  21. Bradford M: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254, 1976

    Google Scholar 

  22. Bélanger A, Caron S, Picard V: Simultaneous radioimmunoassay of progestins, androgens, and estrogens in adult rat testis. J Steroid Biochem 13: 185–190, 1980

    Google Scholar 

  23. Bélanger A, Labrie F, Angeli A: Unconjugated and glucuronide steroid levels in human breast cyst fluid. In: Angeli A, Bradlow HL, Chasalow FI, Gogliotti L (eds) Biochemistry of breast cyst fluid. Correlation with breast cancer risk. Ann NY Acad Sci, vol. 586, pp 93–100, 1990

    Google Scholar 

  24. Kramer CY: Extension of multiple range tests to group means with unique numbers of replications. Biometrics 12: 307–310, 1956

    Google Scholar 

  25. McGuire WL, Carbone PP, Sears ME, Escher GC: Estrogen receptors in human breast cancer: an overview. In: McGuire WL, Carbone PP, Vollmer EP (eds) Estrogen receptors in human breast cancer. Raven Press, New York, 1975, pp 1–7

    Google Scholar 

  26. Poulin R, Labrie F: Stimulation of cell proliferation and estrogenic response by adrenal C19-Δ5-steroids in the ZR-75-1 human breast cancer cell line. Cancer Res 46: 4933–4937, 1986

    Google Scholar 

  27. Henderson BE, Ross R, Bernstein L: Estrogens as a cause of human cancer: The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 48: 246–253, 1988

    Google Scholar 

  28. Poulin R, Simard J, Labrie C, Petitclerc L, Dumont M, Lagacé L, Labrie F: Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line. Endocrinology 125: 392–399, 1989

    Google Scholar 

  29. Poulin R, Baker D, Poirier D, Labrie F: Multiple actions of synthetic ‘progestins’ on the growth of ZR-75-1 human breast cancer cells: anin vitro model for the simultaneous assay of androgen, progestin, estrogen and glucocorticoid agonistic and antagonistic activities of compounds. Breast Cancer Res Treat 17: 197–210, 1991

    Google Scholar 

  30. Siiteri PK, MacDonald PC: The role of extraglandular estrogen in human endocrinology. In: Freiger SR, Astwood EB, Greep RO (eds) Handbook of Physiology, Section 7. The American Physiological Society, New York, 1973, pp 615–619

    Google Scholar 

  31. Labrie F, Simard J, Luu-The V, Trudel C, Martel C, Labrie C, Zhao HF, Rhéaume E, Couët J, Breton N: Expression of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD) in adipose tissue. Int J Obes 15: 91–99, 1991

    Google Scholar 

  32. Milewich L, Garcia RL, Gerrity L: 17β-hydroxysteroid oxidoreductase: an ubiquitous enzyme. Interconversion of estrone and estradiol-17β in BALB/c mouse tissues. Metabolism 34: 938–944, 1985

    Google Scholar 

  33. Luu-The V, Labrie C, Simard J, Lachance Y, Zhao HF, Couët J, Leblanc G, Labrie F: Structure of two in tandem human 17β-hydroxysteroid dehydrogenase genes. Mol Endocrinol 4: 268–275, 1990

    Google Scholar 

  34. Labrie F: Intracrinology. Mol Cell Endocrinol 78: C113-C118, 1991

    Google Scholar 

  35. Prudhomme JF, Malet C, Gompel A, Lalardrie JP, Ochoa C, Boue A, Mauvais-Jarvis P, Kuttenn F: 17β-hydroxysteroid dehydrogenase activity in human breast epithelial cell and fibroblast culture. Endocrinology 114: 1483–1489, 1984

    Google Scholar 

  36. Tait GH, Newton CJ, Reed MJ, James VH: Multiple forms of 17β-hydroxysteroid oxidoreductase in human breast tissue. Mol Endocrinol 2: 71–80, 1989

    Google Scholar 

  37. Thériault C, Labrie F: Hormonal regulation of estradiol 17β-hydroxysteroid dehydrogenase activity in the ZR-75-1 human breast cancer cell line. Ann NY Acad Sci 595: 419–421, 1990

    Google Scholar 

  38. Couture P, Thériault C, Simard J, Labrie F: Androgen receptor-mediated stimulation of 17β-hydroxysteroid dehydrogenase activity by dihydrotestosterone and medroxyprogesterone acetate in ZR-75-1 human breast cancer cells. Endocrinology 132: 179–185, 1993

    Google Scholar 

  39. Bonney RC, Reed MJ, Davidson K, Beranek PA, James VHT: The relationship between 17β-hydroxysteroid dehydrogenase activity and estrogen concentrations in human breast tumors and in normal breast tissue. Clin Endocrinol 19: 727–739, 1983

    Google Scholar 

  40. Vermeulen A, Deslypere JP, Paridaens R, Leclercq G, Roy F, Heuson JC: Aromatase, 17β-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. Eur J Cancer Clin Oncol 22: 515–525, 1986

    Google Scholar 

  41. King RJB, Panattoni M, Gordon J, Baker R: The metabolism of steroids by tissue from normal and neoplastic rat breast. J Endocrinol 33: 127–132, 1965

    Google Scholar 

  42. King RJB, Gordon J, Helfenstein JE: The metabolism of testosterone by tissue from normal and neoplastic rat breast. J Endocrinol 29: 103–110, 1984

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Research Council Group in Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center and Laval University, 2705 Laurier Boulevard, G1V 4G2, Québec, Canada

    Fernand Labrie, Shengmin Li, Claude Labrie, Charles Lévesque & Yves Mérand

Authors
  1. Fernand Labrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shengmin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claude Labrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles Lévesque
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yves Mérand
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Labrie, F., Li, S., Labrie, C. et al. Inhibitory effect of a steroidal antiestrogen (EM-170) on estrone-stimulated growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat. Breast Cancer Res Tr 33, 237–244 (1995). https://doi.org/10.1007/BF00665948

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00665948

Key words

Search

Navigation