Skip to main content

Advertisement

Springer Nature Link
Log in

Drug resistance to tamoxifen during breast cancer therapy

  • William L. McGuire Memorial Symposium
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

Breast cancer is the most common malignancy occurring in Western women, and is one of the leading causes of cancer mortality. The nonsteroidal antiestrogen tamoxifen has been shown to be an effective treatment for pre and postmenopausal women with all stages of the disease. Tamoxifen provides effective palliation when used to treat patients with advanced disease, and adjuvant tamoxifen therapy produces significant increases in both disease-free and overall survival (Early Breast Cancer Trialists Collaborative Group. Lancet 339:1-15, 71-85, 1992). Data from the laboratory have shown that the primary action of tamoxifen is tumoristatic rather than tumoricidal, and long-term therapy is therefore recommended. Unfortunately, many patients experience disease progression while taking tamoxifen. Some tamoxifen resistant tumors may remain sensitive to alternative endocrine therapies, while others may become refractory to any hormonal manipulation. Many models have been developedin vitro andin vivo to study the progression of breast cancer growth from tamoxifen sensitive to tamoxifen resistant. We and others have used long-term estrogen deprivation and long-term tamoxifen exposure to develop cell lines and tumors capable of growth in the presence of clinically relevant tamoxifen concentrations. Recently our laboratory has also shown that mutations in the estrogen receptor can cause an antiestrogen-occupied receptor to behave as though it were occupied by an estrogen. Breast cancer is a highly heterogeneous disease and it is likely that the mechanisms which cause tamoxifen resistant growth are equally heterogeneous. Several of the models from our laboratory and others which may contribute to an understanding of this complex phenomenon are discussed here.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jordan VC, Wolf MF, Mirecki DM, Whitford DA, Welshons WV: Hormone receptor assays: clinical usefulness in the management of carcinoma of the breast. CRC Crit Rev Clin Lab Sci 26:97–152, 1988

    Google Scholar 

  2. Muss HB: Endocrine therapy for advanced breast cancer: a review. Breast Cancer Res Treat 21:15–26, 1992

    Google Scholar 

  3. Early Breast Cancer Trialists Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31000 recurrences and 24000 deaths among 75000 women. Lancet 339:1–15, 71-85, 1992

    Google Scholar 

  4. Wilson AJ: Response in breast cancer to a second hormonal therapy. Revs Endocrine-Related Cancer 14:5–11, 1983

    Google Scholar 

  5. Stoll BA: Second endocrine responses in breast, prostatic and endometrial cancers. Revs Endocrine-Related Cancer 30:19–25, 1988

    Google Scholar 

  6. Legault-Poisson S, Jolivet J, Poisson R, Beretta-Piccoli M, Band PR: Tamoxifen-induced tumor stimulation and withdrawal response. Cancer Treat Rep 63:1839–1841, 1979

    Google Scholar 

  7. Canney PA, Griffiths T, Latief TN, Priestman TJ: Clinical significance of tamoxifen withdrawal response. Lancet i:36, 1987

    Google Scholar 

  8. Katzenellenbogen BS, Kendra KL, Norman MJ, Berthois Y: Proliferation, hormone responsiveness and estrogen receptor content of MCF-7 human breast cancer cells grown in the short-term and long-term absence of estrogens. Cancer Res 47:4355–4360, 1987

    Google Scholar 

  9. Welshons WV, Jordan VC: Adaption of oestrogendependent MCF-7 cells to low oestrogen (phenol redfree) culture. Eur J Cancer Clin Oncol 23:1935–1939, 1987

    Google Scholar 

  10. Wolf DM, Jordan VC: Gynecologic complications associated with long-term adjuvant tamoxifen therapy for breast cancer. Gynecol Oncol 45:118–128, 1992

    Google Scholar 

  11. Fritsch M, Wolf DM: Symptomatic side effects of tamoxifen therapy.In Jordan VC (ed) Long-term tamoxifen treatment for breast cancer. University of Wisconsin Press, Madison (in press)

  12. Nayfield SG, Karp JE, Ford LG, Dorr FA, Kramer BS: Potential role of tamoxifen in prevention of breast cancer. 83:1450-1459, 1991

  13. Satyaswaroop PG, Zaino RJ, Mortel R: Estrogen-like effects of tamoxifen on human endometrial carcinoma transplanted into nude mice. Cancer Res 44:4006–4010, 1984

    Google Scholar 

  14. Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC: Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 48:812–815, 1988

    Google Scholar 

  15. Walker KJ, Price-Thomas JM, Candlish W, Nicholson RI: Influence of the antiestrogen tamoxifen on normal breast tissue. Br J Cancer 64:764–768, 1991

    Google Scholar 

  16. Shafie SM, Grantham FH: Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst 67:51–56, 1981

    Google Scholar 

  17. Osborne CK, Hobbs K, Clark GM: Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic mice. Cancer Res 45:584–590, 1985

    Google Scholar 

  18. Gottardis MM, Robinson SP, Jordan VC: Estradiolstimulated growth of MCF-7 tumors implanted in athymic mice: a model to study the tumoristatic action of tamoxifen. J Steroid Biochem 30:311–314, 1988

    Google Scholar 

  19. Iino Y, Wolf DM, Langan-Fahey SM, Johnson DA, Ricchio M, Thompson ME, Jordan VC: Reversible control of oestradiol-stimulated growth of MCF-7 tumors by tamoxifen in the athymic mouse. Br J Cancer 64:1019–1024, 1991

    Google Scholar 

  20. Osborne CK, Coronado EB, Robinson JP: Human breast cancer in the athymic nude mouse: cytostatic effects of long-term antiestrogen therapy. Eur J Cancer Clin Oncol 23:1189–1196, 1987

    Google Scholar 

  21. Gottardis MM, Jordan VC: Development of tamoxifenstimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48:5183–5187, 1988

    Google Scholar 

  22. Gottardis MM, Wagner RJ, Borden EC, Jordan VC: Differential ability of antiestrogens to stimulate breast cancer cell (MCF-7) growth in vivo and in vitro. Cancer Res 49:4756–4769, 1989

    Google Scholar 

  23. Gottardis MM, Jiang SY, Jeng MH, Jordan VC: Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res 49:4090–4093, 1989

    Google Scholar 

  24. Osborne CK, Coronado E, Allred DC, Wiebe V, DeGregorio M: Acquired tamoxifen (TAM) resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. J Natl Cancer Inst 83:1477–1482, 1991

    Google Scholar 

  25. Osborne CK, Wiebe VJ, McGuire WL, Ciocca DR, DeGregorio M: Tamoxifen and the isomers of 4-hydroxytamoxifen in tamoxifen-resistant tumors from breast cancer patients. J Clin Oncol 10:304–310, 1992

    Google Scholar 

  26. Wiebe VJ, Osborne CK, McGuire WL, DeGregorio MW: Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors. J Clin Oncol 10:990–994, 1992

    Google Scholar 

  27. Langan-Fahey SM, Tormey DC, Jordan VC: Tamoxifen metabolites in patients on long-term adjuvant therapy for breast cancer. Eur J Cancer 26:883–888, 1990

    Google Scholar 

  28. Wolf DM, Langan-Fahey SM, Parker CP, McCague R, Jordan VC: Investigation of the mechanism of tamoxifen stimulated breast tumor growth non-isomerizable analogues of tamoxifen and its metabolites. J Natl Cancer Inst 85:806–812, 1993

    Google Scholar 

  29. Langan-Fahey SM, Jordan VC, Fritz NF, Robinson SP, Waters D, Tormey DC: Clinical pharmacology and endocrinology of long term tamoxifen therapy.In Jordan VC (ed) Long-term tamoxifen treatment for breast cancer. University of Wisconsin Press, Madison (in press)

  30. Jordan VC, Collins MM, Rowsby L, Prestwich G: A monohydroxylated metabolite of tamoxifen with potent antiestrogenic activity. J Endocrinol 73:305–316, 1977

    Google Scholar 

  31. Murphy CS, Langan-Fahey SM, McCague R, Jordan VC: Structure-function relationships of hydroxylated metabolites of tamoxifen that control the proliferation of estrogen-responsive T47D breast cancer cells in vitro. Mol Pharmacol 38:737–743, 1990

    Google Scholar 

  32. McCague R, Kuroda R, LeClerq G, Stoessel S: Synthesis and estrogen receptor binding of 6,7-dihydro-8-phenyl-9-[4-[2-(dimethylamino) ethoxy]phenyl]5H-benzcyclo-heptene, a non-isomerizable analogue of tamoxifen. X-ray crystallographic studies. J Med Chem 29:2053–2058, 1986

    Google Scholar 

  33. Clarke R, Brunner N, Katzenellenbogen BS, Thompson EW, Norman MJ, Koppi C, Paik S, Lippman ME, Dickson RB: Progression of human breast cancer cells from hormone-dependent to hormone-independent growth both in vitro and in vivo. Proc Natl Acad Sci USA 86:3649–3653, 1989

    Google Scholar 

  34. Murphy CS, Pink JJ, Jordan VC: Characterization of a receptor-negative, hormone-nonresponsive clone derived from a T47D human breast cancer cell line kept under estrogen-free conditions. Cancer Res 50:7285–7292, 1990

    Google Scholar 

  35. Daly RJ, Darbre PD: Cellular and molecular events in loss of estrogen sensitivity in ZR-75-1 and T-47-D human breast cancer cells. Cancer Res 50:5868–5875, 1990

    Google Scholar 

  36. Nawata H, Bronzert D, Lippman ME: Isolation and characterization of a tamoxifen-resistant cell line derived from MCF-7 human breast cancer cells. J Biol Chem 256:5016–5021, 1981

    Google Scholar 

  37. Nawata H, Chong MT, Bronzert D, Lippman ME: Estradiol-independent growth of a subline of MCF-7 human breast cancer cells in culture. J Biol Chem 256:6895–6902, 1981

    Google Scholar 

  38. van den Berg HW, Lynch M, Martin J, Nelson J, Dickson GR, Crockard AD: Characterization of a tamoxifen-resistant variant of the ZR-75-1 human breast cancer cell line (ZR-75-9a1) and stability of the resistant phenotype. Br J Cancer 59:522–526, 1989

    Google Scholar 

  39. Bronzert DA, Greene GL, Lippman ME: Selection and characterization of a breast cancer cell line resistant to the antiestrogen LY 117018. Endocrinology 117:1409–1417, 1985

    Google Scholar 

  40. Kasid A, Lippman ME, Papageorge AG, Lowy DR, Gelmann EP: Transfection of v-rasH DNA into MCF-7 human breast cancer cells bypasses dependence on estrogen for tumorigenicity. Science 228:725–728, 1985

    Google Scholar 

  41. Sukumar S, Carney WP, Barbacid M: Independent molecular pathways in initiation and loss of hormone responsiveness of breast carcinomas. Science 240:524–526, 1988

    Google Scholar 

  42. Bronzert DA, Davidson N, Lippman ME: Estrogen and anti-estrogen resistance in human breast cancer cell lines. Adv Exp Med Biol 196:329–345, 1986

    Google Scholar 

  43. Mullick A, Chambon P: Characterization of the estrogen receptor in two antiestrogen-resistant cell lines, LY2 and T47D. Cancer Res 50:333–338, 1990

    Google Scholar 

  44. Pavlik EJ, Nelson K, Srinivasan S, Powell DE, Kenady DE, DePriest PD, Gallion HH, van Nagell JRJ: Resistance to tamoxifen with persisting sensitivity to estrogen: possible mediation by excessive antiestrogen binding site activity. Cancer Res 52:4106–4112, 1992

    Google Scholar 

  45. Agnantis NJ, Parissi P, Anagnostakis D, Spandidos DA: Comparative study of Harvey-ras oncogene expression with conventional clinicopathologic parameters of breast cancer. Oncology 43:36–39, 1986

    Google Scholar 

  46. Jiang S-Y, Wolf DM, Yingling JM, Chang C, Jordan VC: An estrogen receptor positive MCF-7 clone that is resistant to antiestrogens and estradiol. Mol Cell Endocrinol 90:77–86, 1992

    Google Scholar 

  47. McGuire WL, Chamness GC, Fuqua SAW: Estrogen receptor variants in clinical breast cancer. Mol Endocrinol 5:1571–1577, 1991

    Google Scholar 

  48. McGuire WL, Chamness GC, Fuqua SAW: Abnormal estrogen receptor in clinical breast cancer. J Steroid Biochem Mol Biol 43:243–247, 1992

    Google Scholar 

  49. Murphy LC, Dotzlaw H: Variant estrogen receptor mRNA species detected in human breast cancer biopsy samples. Mol Endocrinol 3:687–693, 1989

    Google Scholar 

  50. Dotzlaw H, Alkhalaf M, Murphy LC: Characterization of estrogen receptor variant mRNAs from human breast cancers. Mol Endocrinol 6:773–785, 1992

    Google Scholar 

  51. Graham ML, Krett NL, Miller LA, Leslie KK, Gordon DF, Wood WM, Wei LL, Horwitz KB: T47Dco cells, genetically unstable and containing estrogen receptor mutations, are a model for the progression of breast cancers to hormone resistance. Cancer Res 50:6208–6217, 1990

    Google Scholar 

  52. Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, O'Malley BW, McGuire WL: Variant human breast tumor estrogen receptor with constitutive transcriptional activity. Cancer Res 41:105–109, 1991

    Google Scholar 

  53. Fuqua SAW, Fitzgerald SD, Allred DC, Elledge RM, Nawaz Z, McDonnell DP, O'Malley BW, Greene GL, McGuire WL: Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors. Cancer Res 52:483–486, 1992

    Google Scholar 

  54. Jiang S-Y, Jordan VC: Growth regulation of estrogen receptor-negative breast cancer cells transfected with complementary DNAs for estrogen receptor. J Natl Cancer Inst 84:580–591, 1992

    Google Scholar 

  55. Jiang S-Y, Langan-Fahey SM, Stella AL, McCague R, Jordan VC: Point mutation of estrogen receptor (ER) in the ligand binding domain changes the pharmacology of antiestrogens in ER-negative breast cancer cells stably expressing cDNA's for ER. Mol Endocrinol 6:2167–2194, 1992

    Google Scholar 

  56. Vegeto E, Allan GF, Schrader WT, Tsai M-J, McDonnell DP, O'Malley BW: The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell 69:703–713, 1992

    Google Scholar 

  57. Wilding G, Chen M, Gelman EP: Aberrant responses in vitro of hormone-responsive prostate cancer cells to antiandrogens. Prostate 14:103–115, 1989

    Google Scholar 

  58. Olea N, Sakabe K, Soto AM, Sonnenschein C: The proliferative effect of “anti-androgens” on the androgensensitive human prostate tumor cell line LNCaP. Endocrinology 126:1457–1463, 1990

    Google Scholar 

  59. Schuurmans ALG, Bolt J, Veldscholte J, Mulder E: Stimulatory effects of antiandrogens on LNCaP human prostate tumor cell growth, EGF-receptor level and acid phosphatase secretion. J Steroid Biochem Mol Biol 37:849–853, 1990

    Google Scholar 

  60. Veldscholte J, Voorhorst-Ogink MM, Bolt-de Vries J, van Rooij HCJ, Trapman J, Mulder E: Unusual specificity of the androgen receptor in the human prostate tumor cell line LNCaP: high affinity for progestagenic and estrogenic steroids. Biochim Biophys Acta 1052:187–194, 1990

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, 600 Highland Avenue, 53792, Madison, WI, USA

    Douglas M. Wolf & V. Craig Jordan

Authors
  1. Douglas M. Wolf
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. V. Craig Jordan
    View author publications

    You can also search for this author inPubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wolf, D.M., Jordan, V.C. Drug resistance to tamoxifen during breast cancer therapy. Breast Cancer Res Tr 27, 27–40 (1993). https://doi.org/10.1007/BF00683191

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00683191

Key words