Estrogen and Antiestrogen Resistance in Human Breast Cancer Cell Lines

  • D. A. Bronzert
  • N. Davidson
  • M. Lippman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 196)


Despite nearly a century of awareness of the efficacy of various kinds of endocrine therapies in the management of patients with metastatic breast cancer, many facets of the mechanisms whereby hormones influence the growth of neoplastic tissue remain incompletely understood. Since the initial discovery in 1971 by Jensen et al1 that some breast cancers contain estrogen receptors, substantial progress has been made in understanding the critical role of these hormone binding sites in metabolism and neoplastic growth and in characterizing how these receptors are capable of interacting with nuclear material and activating transcription of specific genes.2,3 Many studies have shown that there is an excellent correlation between the presence of estrogen receptor activity and hormone triggered growth responses in breast tumors.4 Anti-estrogen or high dose estrogen mediated cytotoxicity of breast cancer also requires the presence of an estrogen receptor. Specifically, if the tumor lacks estrogen receptor the chance of seeing an objective response to endocrine therapy is only 5 percent or less. On the other hand, if the tumor contains receptor then the likelihood of a response to endocrine therapy is approximately 50 to 60 percent. Thus, there is a subset of patients who, despite the presence of estrogen binding activity, fail to show a response to endocrine therapy. The present article summarizes current information on cell culture models for this disease entity.


Breast Cancer Estrogen Receptor Progesterone Receptor Human Breast Cancer Cell Human Breast Cancer Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    E. V. Jensen, G. E. Black, S. Smith, K. Kyser, E. R. DeSombre, Estrogen receptors and breast cancer response to adrenalectomy. J. Natl. Cancer Inst. 34: 55 (1971).Google Scholar
  2. 2.
    W. W. Grody, S. T. Schrader, B. W. O’Malley, Activation, transformation, and subunit structure of steroid hormone receptors. Endocr. Review 3: 141 (1982).CrossRefGoogle Scholar
  3. 3.
    K. R. Yamamoto, U. Gehring, M. R. Stampfer, Genetic approaches to steroid hormone actions. Recent Prog. Horm. Res. 32: 3 (1972).Google Scholar
  4. 4.
    W. L. McGuire, P. P. Carbone, M. E. Sears, G. E. Escher, Estrogen receptors in human breast cancer: an overview. In: McGuire WL, Carbone PP, Volmer EP (eds) Estrogen Receptors in Human Breast Cancer. Raven Press, Inc. New York (1975).Google Scholar
  5. 5.
    K. R. Yamamoto, M. R. Stampfer, G. M. Tompkins, Receptors from glucocorticoid-sensitive lymphoma cells and two classes of insensitive clones: physical and DNA-binding properties. Proc. Natl. Acad. Sci. 71: 3901 (1974).PubMedCrossRefGoogle Scholar
  6. 6.
    S. Bourgeois, R. Newby, Diploid and haploid states of the glucocorticoid receptor gene of mouse lymphoid cell lines. Cell 11: 423 (1977).PubMedCrossRefGoogle Scholar
  7. 7.
    J. M. Harmon, E.B. Thompson, Isolation and characterization of Dexamethasone-resistant mutants from human lymphoid cell line CEM-C7. Mol. Cell Biol. 81: 512 (1981).Google Scholar
  8. 8.
    J. E. Griffin, J. D. Wilson, The syndrome of androgen resistance. New Engl. J. Med. 302: 198 (1980).PubMedCrossRefGoogle Scholar
  9. 9.
    H. D. Soule, J. Vazquez, A. Lury, S. Albert, M. Brennan, A human breast cancer line from a pleural effusion derived from a breast carcinoma. J. Natl. Cancer Inst. 51: 1409 (1973).PubMedGoogle Scholar
  10. 10.
    M. E. Lippman, G. Bolan, K. Huff, The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res. 36: 4595 (1976).PubMedGoogle Scholar
  11. 11.
    M. E. Lippman, Definition of hormones and growth factors required for optimal proliferation and expression of phenotypic responses to human breast cells. In: Barnes D (ed) Methods in Molecular and Cell Biology. Alan R. Liss, Inc. New York (in press) (1983).Google Scholar
  12. 12.
    A. Kasid, D. Bronzert, M. E. Lippman, Estradiol responsive human breast cancer cells in culture. In: Aurrichio E (ed) Gonad Steroid Receptors. Field Enterprises, Chicago (in press).Google Scholar
  13. 13.
    M. E. Lippman, G. Bolan, Oestrogen responsive human breast cancer in long-term tissue culture. Nature 256: 592 (1975).PubMedCrossRefGoogle Scholar
  14. 14.
    S. C. Aitken, M. E. Lippman, Hormonal regulation of net DNA synthesis in MCF-7 human breast cancer cells in tissue culture. Cancer Res. 42: 1727 (1982).PubMedGoogle Scholar
  15. 15.
    R. Weichselbaum, S. Hellman, A. Piro, J. Nore, J. Little, Proliferative kinetics of a human breast cancer line in vitro following treatment with 173-estradiol and 1-ß-Darabinofuranosulcytosine. Cancer Res. 38: 2339 (1978).PubMedGoogle Scholar
  16. 16.
    M. J. Page, J. K. Field, N. P. Everett, C. D. Green, Serum regulation of the estrogen responsiveness of the human breast cancer cell line MCF-7. 43: 1244 (1983).Google Scholar
  17. 17.
    B. S. Katzenellenbogen, M. J. Norman, R. L. Eckert, S. W. Peitz, W. F. Mangel, Bioactivities, estrogen receptor interactions, and plasminogen activator-inducing activities of tamoxifen and hydroxy-tamoxifen isomers in MCF-7 human breast cancer cells. Cancer Res 44: 112 (1984).PubMedGoogle Scholar
  18. 18.
    D. Chalbos, F. Vignon, I. Kaydar, H. Rochefort, Estrogens in a human breast cancer cell line (T47D). J. Clin. Endo. Metab. 55: 276 (1982).CrossRefGoogle Scholar
  19. 19.
    W. Yu, B. S. Leung, Y. L. Gao, Effects of 173-estradiol or progesterone receptors and the uptake of thymidine in human breast cancer cell line CAMA-1. Cancer Res. 41: 5004 (1981).PubMedGoogle Scholar
  20. 20.
    C. Natoli, S. Gigliola, V. Natoli, A. Secca, S. Iacobelli, Two new estrogen-supersensitive variants of the MCF-7 human breast cancer cell line. Breast Cancer Res. Treat. 3: 23 (1983).PubMedCrossRefGoogle Scholar
  21. 21.
    D. A. Bronzert, M. E. Monaco, L. Pinkus, S. Aitken, M. E. Lippman, Purification and properties of estrogen responsive cytoplasmic thymidine kinase from human breast cancer. Cancer Res. 41: 604 (1981).PubMedGoogle Scholar
  22. 22.
    S. C. Aitken, M. E. Lippman, Effect of estrogens and anti-estrogens on growth regulatory enzymes in human breast cancer cells in tissue culture. Cancer Res. (in press).Google Scholar
  23. 23.
    K. Cowan, R. Levine, S. Aitken, M. Goldsmith, E. Douglass, N. Clendeninn, A. Nienhuis, M. Lippman, Dihydrofolate reductase gene amplification and possible rearrangement in estrogen-responsive methotrexate-resistant human breast cancer cells. J. Biol. Chem. 257: 15079 (1982).PubMedGoogle Scholar
  24. 25.
    R. E. Burke, S. C. Harris, W. L. McGuire, Lactate dehydrogenase in estrogen-responsive human breast cancer cells. Cancer Res. 38: 2773 (1978).Google Scholar
  25. 26.
    B. Westley, H. Rochefort, A secreted glycoprotein induced by estrogen in human breast cancer cell lines. Cell 20: 353 (1980).PubMedCrossRefGoogle Scholar
  26. 27.
    D. P. Edwards, D. J. Adams, W. L. McGuire, Estradiol stimulates synthesis of a major intracellular protein in a human breast cancer cell line (MCF-7). Breast Cancer Res. Treat. 1: 209 (1981).PubMedCrossRefGoogle Scholar
  27. 28.
    P. Maisiakowski, R. Breathnach, J. Block, F. Gannon, A. Krast, P. Chambon, Cloning of cDNA sequences of hormone-regulated genes from the MCF-7 human breast cancer cell line. Nucleic Acids Res. 24: 7895 (1982).CrossRefGoogle Scholar
  28. 29.
    K. Siebert, S. Shafie, T. Triche, J. Whang-Peng, S. O’Brien, J. Toney, K. Huff, M. Lipman, Clonal variation of MCF-7 breast cancer cells in vitro and in athymic nude mice. Cancer Res. 43: 2223 (1983).Google Scholar
  29. 30.
    D. A. Bronzert, G. L. Greene, M. E. Lippman, Selection and characterization of a breast cancer cell line resistant to the anti-estrogen LY 117018. Endocrinology (submitted).Google Scholar
  30. 31.
    K. B. Horwitz, W. L. McGuire, Estrogen control of progesterone receptor in human breast cancer. J. Biol. Chem. 253: 2223 (1978).PubMedGoogle Scholar
  31. 32.
    S. M. Scholl, K. K. Huff, M. E. Lippman, Anti-estrogenic effects of LY 117018 in MCF-7 cells. Endocrinology 113: 611 (1983).PubMedCrossRefGoogle Scholar
  32. 33.
    E. K. Watts, L. C. Murphy, R. L. Sutherland, Microsomal binding sites for non-steroidal anti-estrogens in MCF-7 human mammary carcinoma cells. J. Biol. Chem. 259: 4223 (1984).PubMedGoogle Scholar
  33. 34.
    L. J. Black, R. L. Goode, Evidence for biological action of the antiestrogens LY 117018 and tamoxifen by different mechanisms. 109: 987 (1981).Google Scholar
  34. 35.
    R. M. Hillman, W. B. Butler, Sensitivity of clones of the human breast cancer cell line MCF-7 to the anti-estrogens tamoxifen and 4-0H tamoxifen. Amer. Assoc. Cancer Res. 25: 205 (abstract) (1984).Google Scholar
  35. 36.
    W. B. Butler, W. H. Kelsey, N. Goran, Effect of serum and insulin on the sensitivity of the human breast cancer cell line MCF-7 to estrogen and anti-estrogens 41: 82 (1981).Google Scholar
  36. 37.
    L. J. Brandes, M. W. Hermonat, Receptor status and subsequent sensitivity of subclones of MCF-7 human breast cancer cells surviving exposure to diethylstilbestrol. Cancer Res. 43: 2831 (1983).PubMedGoogle Scholar
  37. 38.
    D. Bronzert, R. B. Hochberg, M. E. Lippman, Specific cytotoxicity of 16-[125I]iodoestradiol for estrogen receptor-containing breast cancer cells. Endocrinology 110: 2177 (1982).PubMedCrossRefGoogle Scholar
  38. 39.
    D. A. Bronzert, T. J. Triche, P. Gleason, M. E. Lippman, Isolation and characterization of an estrogen inhibited variant from the MCF-7 breast cancer cell line. Cancer Res. 44: 3942 (1984).PubMedGoogle Scholar
  39. 40.
    R. Jakesz, C. A. Smith, S. Aitken, K. Huff, W. Schuette, S. Shackney, M. Lippman, Influence of cell proliferation and cell cycle phase on expression of estrogen receptor in MCF-7 cells. Cancer Res. 44: 619 (1984).PubMedGoogle Scholar
  40. 41.
    N. Brunner, M. Spang-Thomsen, L. Vindelov, A. Nielson, Effect of l70,-estradiol on growth curves and flow cytometric DNA distribution of two human breast carcinomas grown in nude mice. Br. J. Cancer 47: 641 (1983).PubMedCrossRefGoogle Scholar
  41. 42.
    N. Brunner, M. Spant-Thomsen, L. Vindelow, A. Nielson, S. Engelholm, Svenstrump, Dose-dependent effect of 171-estradiol determined by growth curves and flow cytometric DNA analysis of a human breast carcinoma (T61) grown in nude mice. Exp. Cell Biol. (in press) (1984).Google Scholar
  42. 43.
    H. Nawata, D. Bronzert, M.E. Lippman, Isolation and characterization of a tamoxifen-resistant cell line derived from MCF-7 human breast cancer cells. J. Biol. Chem. 256: 5016 (1981).PubMedGoogle Scholar
  43. 44.
    H. Nawata, M. J. Chong, D. Bronzert, M.E. Lippman, Estradiolindependent growth of a subline of MCF-7 human breast cancer cells in culture. J. Biol. Chem. 256: 6895 (1981).PubMedGoogle Scholar
  44. 45.
    M. A. Miller, M. E. Lippman, B. Katzenellenbogen. Anti-estrogen binding in anti-estrogen growth resistant estrogen-responsive clonal variants of MCF-7 human breast cancer cells. Cancer Res. 44: 5038 (1984).PubMedGoogle Scholar
  45. 46.
    F. Vignon, M. E. Lippman, H. Nawata, D. Derocq and H. Rochefort, Induction of two estrogen-responsive proteins by anti-estrogens in R27, a Tamoxifen-resistant clone of MCF-7 cells. Cancer Res. 44: 2084 (1984).PubMedGoogle Scholar
  46. 47.
    L. J. Black, R. L. Goode, Uterine bioassay of tamoxifen, trioxifene, and a new estrogen antagonist (LY 117018) in rats and mice. Life Sci. 26: 1453 (1980).PubMedCrossRefGoogle Scholar
  47. 48.
    R. J. Kaufman, P. C. Brown, R. T. Schimke, Amplified dihydrofo-late stimulate cell proliferation and induce secretory proteins reductase genes in unstably methotrexate-resistant cells are associated with double minute chromosomes. Proc. Natl. Acad. Sci. USA 76: 5669 (1979).Google Scholar
  48. 49.
    K. B. Horwitz, D. T. Zava, A. K. Thilager, E. M. Jensen, W. L. McGuire, Steroid receptor analyses of nine human breast cancer cell lines. Cancer Res. 38: 2434 (1978).PubMedGoogle Scholar
  49. 50.
    W. W. Leavitt, T. J. Chen, T. C. Allen, Regulation of progesterone receptor formation by estrogen action. Ann NY Acad Sci 286: 210 (1977).PubMedCrossRefGoogle Scholar
  50. 51.
    B. Westley, F. May, T. Brown, A. Krust, P. Chambon, M. Lippman and H. Rochefort, Effects of anti-estrogens on the estrogen regulated pS2 RNA, 52K and 160K proteins in MCF-7 cells and two tamoxifen resistant sublines. J. Biol. Chem. 259: 10030 (1984).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • D. A. Bronzert
    • 1
  • N. Davidson
    • 1
  • M. Lippman
    • 1
  1. 1.Medical Breast Cancer SectionNational Cancer Institute National Institutes of HealthBethesdaUSA

Personalised recommendations