Skip to main content
SpringerLink
Log in

Medroxyprogesterone acetate inhibits the proliferation of estrogen- and progesterone-receptor negative MFM-223 human mammary cancer cells via the androgen receptor

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

Summary

This study demonstrates for the first time, that medroxyprogesterone acetate (MPA) inhibits the proliferation of the estrogen and progesterone receptor negative mammary cancer cell line MFM-223 via the androgen receptor. MPA is a progestin, which is used in the hormonal treatment of disseminated breast cancer. It binds to the progesterone, androgen, and glucocorticoid receptor and may exert its antiproliferative effects via different receptors. MFM-223 human mammary cancer cells contain a very high level of androgen receptors (160 fmol/mg protein) and low levels of estrogen, progesterone, and glucocorticoid receptors (<20 fmol/mg protein). This cell line provides therefore a good model system to analyze the possible role of the androgen receptor in the action of MPA avoiding interference with other steroid hormone receptors. Effective inhibition of proliferation is achieved by 10 nM MPA or 1 nM of the androgen dihydrotestosterone, corresponding well to the binding affinities of both compounds (3.6 and 0.18 nM, respectively). The involvement of the androgen receptor was confirmed by competition experiments with antiandrogens. Furthermore, MFMDHT cells, which are an androgen resistant subline of MFM-223 cells, are also resistant to MPA. This data supports the involvement of the androgen receptor in the action of MPA and additionally rules out direct hormone-independent cytotoxic effects of MPA.

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. Blossey HC, Wander HE, Köbberling J, Nagel GA: Pharmacokinetic and pharmacodynamic basis for the treatment of metastatic breast cancer with high dose medroxyprogesterone acetate. Cancer 54: 1208–1215, 1984

    Google Scholar 

  2. Becher R, Miller AA, Höffken K, Gerhold U, Hirche H, Schmidt CG: High-dose medroxyprogesterone-acetate in advanced breast cancer. Clinical and pharmakokinetic study with a combined oral and intramuscular regimen. Cancer 63: 1938–1943, 1989

    Google Scholar 

  3. Schulz K-D, Schmidt-Rhode P, Zippel HH, Sturm G: New concepts of adjuvant drug treatment in endometrial cancer. In: Schulz K-D, King RJB, Pollow K, Taylor RW (eds) Endometrial cancer. Zuckschwerdt, Munich, Vienna, San Francisco, 1987, pp 169–180

    Google Scholar 

  4. Hellman L, Yoshida K, Zumoff B, Levin J, Kream J, Fukushima DK: The effect of medroxyprogesterone acetate on the pituitary-adrenal axis. J Clin Endocrinol Metab 42: 912–917, 1976

    Google Scholar 

  5. DiMarco A: The antitumor activity of 6-methyl-17-acetoxy progesterone (MPA) in experimental mammary cancer. In: Iacobelli S, DiMarco A (eds) Role of Medroxyprogesterone in endocrine-related tumors. Raven Press, New York, 1980, pp 1–20

    Google Scholar 

  6. Braunsberg H, Coldham N, Leake R, Cowan S, Wong W: Actions of a progestogen on human breast cancer cells: Mechanism of growth stimulation and inhibition. Eur J Cancer Clin Oncol 5: 563–571, 1987

    Google Scholar 

  7. Sutherland RL, Hall RE, Pang GYN, Musgrove EA, Clarke CL: Effect of medroxyprogesterone acetate on proliferation and cell cycle kinetics of human mammary carcinoma cells. Cancer Res 48: 5084–5091, 1988

    Google Scholar 

  8. Hackenberg R, Hofmann J, Wolff G, Hölzel F, Schulz K-D: Down-regulation of androgen receptor by progestins and interference with estrogenic and androgenic stimulation of cell growth. J Cancer Res Clin Oncol 116: 492–498, 1990

    Google Scholar 

  9. Horwitz KB, Costlow ME, McGuire WL: A human breast cancer cell line with estrogen, androgen, progesterone and glucocorticoid receptors. Steroids 26: 785–795, 1975

    Google Scholar 

  10. Keydar I, Chen L, Karby S, Weiss FR, Delarea J, Radu M, Chaitcik S, Brenner HJ: Establishment and characterization of a cell line of human breast carcinoma origin. Eur J Cancer 15: 659–670, 1979

    Google Scholar 

  11. Engel LW, Young NA, Tralka TS, Lippman ME, O'Brien SJ, Joyce MJ: Establishment and characterization of three new continuous cell lines derived from human breast carcinomas. Cancer Res 38: 3352–3364, 1978

    Google Scholar 

  12. Simon WE, Albrecht M, Trams G, Dietel M, Hölzel F:In vitro growth promotion of human mammary carcinoma cells by steroid hormones, tamoxifen and prolactin. J Natl Cancer Inst 73: 313–321, 1984

    Google Scholar 

  13. Hackenberg R, Lüttchens S, Hofmann J, Kunzmann R, Hölzel F, Schulz K-D: Androgen sensitivity of the new human breast cancer cell line MFM-223. Cancer Res 51: 5722–5727, 1991

    Google Scholar 

  14. Teulings FAG, van Gilse HA, Henkelman MS, Portengen H, Alexieva-Figusch J: Estrogen, androgen, glucocorticoid, and progesterone receptors in progestin-induced regression of human breast cancer. Cancer Res 40: 2557–2561, 1980

    Google Scholar 

  15. Young PCM, Keen FK, Einhorn LH, Stanick BM, Ehrlich CE, Cleary RE: Binding of medroxyprogesterone acetate in human breast cancer. Am J Obstet Gynecol 137: 284–292, 1980

    Google Scholar 

  16. Darbre P, Yates J, Curtis S, King RJB: Effect of estradiol on human breast cancer cellsin vitro. Cancer Res 43: 349–354, 1983

    Google Scholar 

  17. Hackenberg R, Hawighorst Th, Filmer A, Slater EP, Bock K, Beato M, Schulz K-D: Regulation of androgen receptor mRNA and protein level by steroid hormones in human mammary cancer cells. J Steroid Biochem Mol Biol 43: 599–607, 1992

    Google Scholar 

  18. Dixon M, Webb C: Enzymes. 2nd ed. Longman, London, 1971

    Google Scholar 

  19. Lippman ME, Bolan G, Huff K: The effect of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 36: 4595–4601, 1976

    Google Scholar 

  20. Lippman ME, Bolan G, Huff K: The effect of glucocorticoids and progesterone on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 36: 4602–4609, 1976

    Google Scholar 

  21. Lippman ME, Bolan G, Huff K: The effect of androgens and antiandrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 36: 4610–4618, 1976

    Google Scholar 

  22. Chalbos D, Vignon F, Keydar I, Rochefort H: Estrogens stimulate cell proliferation and induce secretory proteins in a human breast cancer cell line (T47D). J Clin Endocrinol Metab 55: 276–283, 1982

    Google Scholar 

  23. Simon WE, Hänsel M, Dietel M, Matthiesen L, Albrecht M, Hölzel F: Alteration of steroid hormone sensitivity during the cultivation of human mammary carcinoma cells.In vitro 20: 157–166, 1984

    Google Scholar 

  24. Leung BS, Potter AH, Qureshi S: Interactions of prolactin, estrogen, and progesterone in a human mammary carcinoma cell line, CAMA-1-I. Cell growth and thymidine uptake. J Steroid Biochem 15: 421–427, 1981

    Google Scholar 

  25. Vignon F, Bardon S, Chalbos D, Rochefort H: Antiestrogenic effect of R5020, a synthetic progestin in human breast cancer cells in culture. J Clin Endocrinol Metab 56: 1124–1130, 1983

    Google Scholar 

  26. Poulin R, Baker D, Labrie F: Androgens inhibit basal and estrogen-induced proliferation in the ZR-75-1 human breast cancer cell line. Breast Cancer Res Treat 12: 213–225, 1988

    Google Scholar 

  27. Poulin R, Dufour JM, Labrie F: Progestin inhibition of estrogen-dependent proliferation in ZR-75-1 human breast cancer cells: antagonism by insulin. Breast Cancer Res Treat 13: 265–276, 1989

    Google Scholar 

  28. Osborne CK, Monaco ME, Kahn CR, Huff K, Bronzert D, Lippman ME: Direct inhibition of growth and antagonism by glucocorticoids in human breast cancer cells in culture. Cancer Res 39: 2422–2428, 1979

    Google Scholar 

  29. Poulin R, Baker D, Poirier D, Labrie F: Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells. Breast Cancer Res Treat 13: 161–172, 1989

    Google Scholar 

  30. 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 steroids. Breast Cancer Res Treat 17: 197–210, 1990

    Google Scholar 

  31. Maass H, Engel B, Trams G: Steroid hormone receptors in human breast cancer and the clinical significance. J Steroid Biochem 6: 743–749, 1975

    Google Scholar 

  32. Würz H, Schulz K-D, Citoler P, Kaiser R: Verteilung von Östrogen-, Gestagen-, Androgen- und Kortikosteroidrezeptoren in Mammakarzinomen. In: Jonat W, Maas H (eds) Steroidhormonrezeptoren im Karzinomgewebe. Enke, Stuttgart, 1982, pp 23–30

    Google Scholar 

  33. Lea OA, Kvinnsland S, Thorsen T: Improved measurement of androgen receptors in human breast cancer. Cancer Res 49: 7162–7167, 1989

    Google Scholar 

  34. van Veelen H, Willemse PHB, Sleijfer DT, Sluiter WJ, Doorenbos H: Endocrine effects of medroxyprogesterone acetate: Relation between plasma levels and suppression of adrenal steroids in patients with breast cancer. Cancer Treat Rep 69: 977–983, 1985

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Zentrum für Frauenheilkunde und Geburtshilfe, Philipps Universität, Pilgrimstein 3, W-3550, Marburg, Germany

    Reinhard Hackenberg, Thomas Hawighorst, Angelika Filmer, Abdolhamid Huschmand Nia & Klaus-Dieter Schulz

Authors
  1. Reinhard Hackenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Hawighorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angelika Filmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abdolhamid Huschmand Nia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Klaus-Dieter Schulz
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Dedicated to Prof. Dr. Heinrich Maass, Director of the Department of Obstetrics and Gynecology of the University of Hamburg, on the occasion of his 65th birthday.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hackenberg, R., Hawighorst, T., Filmer, A. et al. Medroxyprogesterone acetate inhibits the proliferation of estrogen- and progesterone-receptor negative MFM-223 human mammary cancer cells via the androgen receptor. Breast Cancer Res Tr 25, 217–224 (1993). https://doi.org/10.1007/BF00689836

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00689836

Key words

Search

Navigation