Cancer Chemotherapy and Pharmacology

, Volume 35, Issue 2, pp 149–152 | Cite as

Reduced tamoxifen accumulation is not associated with stimulated growth in tamoxifen resistance

  • Juhani Maenpaa
  • Valerie Wiebe
  • Gregory Wurz
  • Steven Koester
  • Vernon Emshoff
  • Robert Seymour
  • Michael DeGregorio
Original Article Tamoxifen, Resistance, Breast Cancer


To study tamoxifen resistance-stimulated growth, 30 female ovariectomized nude mice were implanted with tamoxifen-resistant tumors and treated with 10–1000 μg/day of tamoxifen citrate subcutaneously. Tamoxifen stimulated MCF-7 tumor growth in a dose-dependent manner, with tumoral tamoxifen concentrations increasing proportionally to the dose (1–13 nmol/g), as measured by high-performance liquid chromatography (HPLC). Flow-cytometric analysis revealed that tamoxifen-resistant tumors had a different DNA content as compared with wild-type MCF-7 cells. In contrast to earlier results, these data suggest that tamoxifen resistance-stimulated growth is associated with increasing rather than decreasing tumoral tamoxifen concentrations. Furthermore, the observed ploidy changes in the tamoxifen-resistant tumors imply that a genetic basis may exist for the development of tamoxifen resistance.

Key words

Breast Cancer Tamoxifen Resistance 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Baker WJ, Wiebe VJ, Koester SK, Emshoff VD, Maenpaa JU, Wurz GT, DeGregorio MW (1992) Monitoring the chemosensitizing effects of toremifene with flow cytometry in estrogen receptor negative multidrug resistant breast cancer cells. Breast Cancer Res Treat 24: 43Google Scholar
  2. 2.
    Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156Google Scholar
  3. 3.
    Fendl K, Zimniski SJ (1992) Role of tamoxifen in the induction of hormone-independent rat mammary tumors. Cancer Res 52: 235Google Scholar
  4. 4.
    Gottardis MM, Jordan VC (1988) Development of tamoxifen stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48: 5183Google Scholar
  5. 5.
    Gottardis MM, Jiang SY, Jeng M-H, Jordan VC (1989) Inhibition of tamoxifen stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res 49: 4090Google Scholar
  6. 6.
    Horwitz KB (1993) Mechanisms of hormone resistance in breast cancer. Breast Cancer Res Treat 26: 119Google Scholar
  7. 7.
    Johnston SRD, Haynes BP, Smith IE, Jarman M, Sacks NPM, Ebbs SR, Dowsett M (1993) Acquired tamoxifen resistance in human breast cancer and reduced intra-tumoral drug concentration. Lancet 342: 1521Google Scholar
  8. 8.
    Krishan A (1975) Rapid flow-cytometric analysis of mammalian cell cycle by propidium iodide staining. J Cell Biol 66: 188Google Scholar
  9. 9.
    Maenpaa J, Wiebe V, Koester S, Wurz G, Emshoff V, Seymour R, Sipila P, DeGregorio M (1993) Tamoxifen stimulates in vivo growth of drug-resistant estrogen receptor-negative breast cancer. Cancer Chemother Pharmacol 32: 396Google Scholar
  10. 10.
    Maenpaa JU, Wurz GT, Baker WJ, Wiebe VJ, Emshoff VD, Koester SK, Seymour RC, Koehler RE, DeGregorio MW (1994) A breast cancer clone selected by tamoxifen has increased growth rate and reduced sensitivity to doxorubicin. Oncol Res 5(12): 461Google Scholar
  11. 11.
    Osborne CK, Coronado EB, Robinson JP (1987) Human breast cancer in the athymic nude mouse: cytostatic effects of long-term antiestrogen therapy. Eur J Cancer Clin Oncol 23: 1189Google Scholar
  12. 12.
    Osborne CK, Coronado E, Allred DC, Wiebe V, DeGregorio M (1991) Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. J Natl Cancer Inst 83: 1477Google Scholar
  13. 13.
    Pastan I, Gottesman M (1987) Multiple-drug resistance in human cancer. N Engl J Med 316: 1388Google Scholar
  14. 14.
    Pritchard KI, Thomson DB, Myers RE, Sutherland DJA, Mobbs BG, Meakin JW (1980) Tamoxifen therapy in premenopausal patients with metastatic breast cancer. Cancer Treat Rep 64: 787Google Scholar
  15. 15.
    Ramu A, Glaubiger D, Fuks Z (1984) Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by tamoxifen and other triparanol analogues. Cancer Res 44: 4392Google Scholar
  16. 16.
    Sipila PEH, Wiebe VJ, Hubbard GB, Koester SK, Emshoff VD, Maenpaa JU, Wurz GT, Seymour RC, DeGregorio MW (1993) Prolonged tamoxifen exposure selects a breast-cancer cell clone that is stable in vitro and in vivo. Eur J Cancer 29A: 2138Google Scholar
  17. 17.
    Taylor SG, Gelman RS, Falkson G, Cummings FJ (1986) Combination chemotherapy compared with tamoxifen as initial therapy for stage IV breast cancer in elderly women. Ann Intern Med 104: 455Google Scholar
  18. 18.
    Wiebe V, Osborne CK, McGuire WL, DeGregorio MW (1992) Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors. J Clin Oncol 10: 990Google Scholar
  19. 19.
    Wiebe VJ, Osborne CK, Fuqua SAW, DeGregorio MW (1993) Tamoxifen resistance in breast cancer. CRC Crit Rev Oncol Hematol 14: 173Google Scholar
  20. 20.
    Wolf DM, Langan-Fahey SM, Parker CJ, McCague R, Jordan VC (1993) Investigation of the mechanism of tamoxifen-stimulated breast tumor growth with nonisomerizable analogues of tamoxifen and metabolites. J Natl Cancer Inst 85: 806Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Juhani Maenpaa
    • 1
    • 2
  • Valerie Wiebe
    • 1
  • Gregory Wurz
    • 1
  • Steven Koester
    • 1
  • Vernon Emshoff
    • 1
  • Robert Seymour
    • 1
  • Michael DeGregorio
    • 3
  1. 1.Department of Medicine, Division of OncologyUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  2. 2.Department of Obstetrics and GynecologyUniversity of TurkuTurkuFinland
  3. 3.Cancer Center, Division of Hem/Oncol.Univ. of California at DavisSacramentoUSA

Personalised recommendations