Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Endocrine-responsive breast cancer and strategies for combating resistance

Nature Reviews Cancer volume 2, pages 101–112 (2002)Cite this article

Key Points

  • Breast cancer is the most common cancer of women in the western world. In most cases, breast cancer is oestrogen dependent, and treatment with oestrogen antagonists that inhibit oestrogen receptor (ER) action, particularly tamoxifen, has contributed to a dramatic reduction in breast cancer mortality. However, a substantial proportion of patients presenting with localized disease, and all of the patients with metastatic disease, become resistant to endocrine therapies.

  • In most cases, the ER is present in resistant tumours, and in many of these its activity continues to regulate tumour growth.

  • Resistance to endocrine therapy potentially arises by: ER activation in the absence of oestrogen; hypersensitivity of ER to low levels of circulating oestrogens; or ER activation, rather than inhibition, by oestrogen antagonists.

  • At the molecular level, mechanisms responsible for resistance include:

  • ER mutations that result in increased sensitivity to ligand and/or co-activator recruitment, and a resultant increase in ER activity.

  • Post-translational modifications that result in ligand-independent activation of the ER. These modifications can be triggered by the oncogenic activation of growth-factor signalling pathways.

  • Increased expression of the co-activator proteins that mediate ER activity. By contrast, downregulation of corepressor activity reduces the inhibitory potential of tamoxifen.

  • Mitogenic and anti-apoptotic effects can be mediated by non-genomic effects of the ER, through direct interaction with key components of several signal-transduction pathways. Altered activity of these pathways could contribute to resistance.

  • By understanding which of these pathways could be involved in mediating resistance, we might be able to develop strategies for overcoming or bypassing such resistance.

Abstract

Deaths from breast cancer have fallen markedly over the past decade due, in part, to the use of endocrine agents that reduce the levels of circulating oestrogens or compete with oestrogen for binding to its receptor. However, many breast tumours either fail to respond or become resistant to endocrine therapies. By understanding the mechanisms that underlie this resistance, we might be able to develop strategies for overcoming or bypassing it.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure of normal and malignant breast tissue.
Figure 2: Mechanisms of action of therapeutic agents used in endocrine therapy.
Figure 3: Treatment regimes for oestrogen-receptor-positive breast cancer.
Figure 4: Mechanisms of oestrogen-receptor activation.
Figure 5: Structure of the oestrogen-receptor ligand-binding domain.
Figure 6: Post-translational modification of the oestrogen receptor.
Figure 7: Non-genomic actions of the oestrogen receptor.

References

  1. Kelsey, J. L. & Berkowitz, G. S. Breast cancer epidemiology. Cancer Res. 48, 5615–5623 (1988).

    CAS  PubMed  Google Scholar 

  2. Beatson, G. T. On the treatment of inoperable cases of carcinoma of the mammary. Suggestions for a new method of treatment with illustrative cases. Lancet 2, 104–107, 162–165 (1896).

    Google Scholar 

  3. Osborne, C. K. Tamoxifen in the treatment of breast cancer. N. Engl. J. Med. 339, 1609–1618 (1998).

    CAS  PubMed  Google Scholar 

  4. MacGregor, J. I. & Jordan, V. C. Basic guide to the mechanisms of antiestrogen action. Pharmacol. Rev. 50, 151–196 (1998).

    CAS  PubMed  Google Scholar 

  5. Buzdar, A. & Howell, A. Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer. Clin. Cancer Res. 7, 2620–2635 (2001).

    CAS  PubMed  Google Scholar 

  6. Russo, J. & Russo, I. H. in The Mammary Gland: Development, Regulation and Function (eds Neville, M. C. & Daniel, C. W.) (Plenum, New York, 1987).

    Google Scholar 

  7. Russo, J. & Russo, I. H. Toward a physiological approach to breast cancer prevention. Cancer Epidemiol. Biomarkers Prev. 3, 353–364 (1994).

    CAS  PubMed  Google Scholar 

  8. Cunha, G. R. et al. Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombinants. J. Mammary Gland Biol. Neoplasia 2, 393–402 (1997).

    CAS  PubMed  Google Scholar 

  9. Ricketts, D. et al. Estrogen and progesterone receptors in the normal female breast. Cancer Res. 51, 1817–1822 (1991).

    CAS  PubMed  Google Scholar 

  10. Anderson, E., Clarke, R. B. & Howell, A. Estrogen responsiveness and control of normal human breast proliferation. J. Mammary Gland Biol. Neoplasia 3, 23–35 (1998).

    CAS  PubMed  Google Scholar 

  11. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Lakhani, S. R. The transition from hyperplasia to invasive carcinoma of the breast. J. Pathol. 187, 272–278 (1999).

    CAS  PubMed  Google Scholar 

  13. Clarke, R. B., Howell, A., Potten, C. S. & Anderson, E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res. 57, 4987–4991 (1997).

    CAS  PubMed  Google Scholar 

  14. Russo, J., Ao, X., Grill, C. & Russo, I. H. Pattern of distribution of cells positive for estrogen receptor-α and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res. Treat. 53, 217–227 (1999). References 13 and 14 show that in the normal breast, ER-positive cells are non-proliferative.

    CAS  PubMed  Google Scholar 

  15. Simpson, E. R. & Davis, S. R. Minireview: aromatase and the regulation of estrogen biosynthesis — some new perspectives. Endocrinology 142, 4589–4594 (2001).

    CAS  PubMed  Google Scholar 

  16. Pasqualini, J. R. et al. Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. J. Clin. Endocrinol. Metab. 81, 1460–1464 (1996).

    CAS  PubMed  Google Scholar 

  17. Castagnetta, L. A. et al. Estrogen content and metabolism in human breast tumor tissues and cells. Ann. NY Acad. Sci. 784, 314–324 (1996).

    CAS  PubMed  Google Scholar 

  18. Safe, S. H. Interactions between hormones and chemicals in breast cancer. Annu. Rev. Pharmacol. Toxicol. 38, 121–158 (1998).

    CAS  PubMed  Google Scholar 

  19. Clemons, M. & Goss, P. Estrogen and the risk of breast cancer. N. Engl. J. Med. 344, 276–285 (2001).

    CAS  PubMed  Google Scholar 

  20. Cavalieri, E. L. et al. Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc. Natl Acad. Sci. USA 94, 10937–10942 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang, C. S. et al. Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res. 59, 4870–4875 (1999).

    CAS  PubMed  Google Scholar 

  22. Khan, S. A., Rogers, M. A., Khurana, K. K., Meguid, M. M. & Numann, P. J. Estrogen receptor expression in benign breast epithelium and breast cancer risk. J. Natl Cancer Inst. 90, 37–42 (1998). Identifies a link between ER expression in the benign breast and breast cancer risk.

    CAS  PubMed  Google Scholar 

  23. Markopoulos, C., Berger, U., Wilson, P., Gazet, J. C. & Coombes, R. C. Oestrogen receptor content of normal breast cells and breast carcinomas throughout the menstrual cycle. Br Med J 296, 1349–1351 (1988).| PubMed |

    CAS  Google Scholar 

  24. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351, 1451–1467 (1998).

  25. Klijn, J. G. et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J. Clin. Oncol. 19, 343–353 (2001).

    CAS  PubMed  Google Scholar 

  26. Coombes, R. C. et al. Idoxifene: report of a phase I study in patients with metastatic breast cancer. Cancer Res. 55, 1070–1074 (1995).

    CAS  PubMed  Google Scholar 

  27. Howell, A. et al. Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer. Br. J. Cancer 74, 300–308 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mangelsdorf, D. J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Schwabe, J. W., Chapman, L., Finch, J. T. & Rhodes, D. The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements. Cell 75, 567–578 (1993).

    CAS  PubMed  Google Scholar 

  30. Tsai, M. J. & O'Malley, B. W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu. Rev. Biochem. 63, 451–486 (1994).

    CAS  PubMed  Google Scholar 

  31. Smith, C. L. Cross-talk between peptide growth factor and estrogen receptor signaling pathways. Biol. Reprod. 58, 627–632 (1998).

    CAS  PubMed  Google Scholar 

  32. Gronemeyer, H. Transcription activation by estrogen and progesterone receptors. Annu. Rev. Genet. 25, 89–123 (1991).

    CAS  PubMed  Google Scholar 

  33. Sadovsky, Y. et al. Transcriptional activators differ in their responses to overexpression of TATA-box-binding protein. Mol. Cell. Biol. 15, 1554–1563 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ing, N. H., Beekman, J. M., Tsai, S. Y., Tsai, M. J. & OqMalley, B. W. Members of the steroid hormone receptor superfamily interact with TFIIB (S300-II). J. Biol. Chem. 267, 17617–17623 (1992).

    CAS  PubMed  Google Scholar 

  35. Jacq, X. et al. Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor. Cell 79, 107–117 (1994).

    CAS  PubMed  Google Scholar 

  36. Glass, C. K. & Rosenfeld, M. G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 (2000).

    CAS  PubMed  Google Scholar 

  37. McKenna, N. J. & O'Malley, B. W. From ligand to response: generating diversity in nuclear receptor coregulator function. J. Steroid Biochem. Mol. Biol. 74, 351–356 (2000).

    CAS  PubMed  Google Scholar 

  38. Kingston, R. E. & Narlikar, G. J. ATP-dependent remodeling and acetylation as regulators of chromatin fluidity. Genes Dev. 13, 2339–2352 (1999).

    CAS  PubMed  Google Scholar 

  39. Workman, J. L. & Kingston, R. E. Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu. Rev. Biochem. 67, 545–579 (1998).

    CAS  PubMed  Google Scholar 

  40. Sudarsanam, P. & Winston, F. The Swi/Snf family nucleosome-remodeling complexes and transcriptional control. Trends Genet. 16, 345–351 (2000).

    CAS  PubMed  Google Scholar 

  41. Ito, M. & Roeder, R. G. The TRAP/SMCC/mediator complex and thyroid hormone receptor function. Trends Endocrinol. Metab. 12, 127–134 (2001).

    CAS  PubMed  Google Scholar 

  42. Grunstein, M. Histone acetylation in chromatin structure and transcription. Nature 389, 349–352 (1997).

    CAS  PubMed  Google Scholar 

  43. Struhl, K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 12, 599–606 (1998).

    CAS  PubMed  Google Scholar 

  44. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    CAS  PubMed  Google Scholar 

  45. McKenna, N. J., Lanz, R. B. & O'Malley, B. W. Nuclear receptor coregulators: cellular and molecular biology. Endocr. Rev. 20, 321–344 (1999).

    CAS  PubMed  Google Scholar 

  46. Leo, C. & Chen, J. D. The SRC family of nuclear receptor coactivators. Gene 245, 1–11 (2000).

    CAS  PubMed  Google Scholar 

  47. Bannister, A. J. & Kouzarides, T. The CBP co-activator is a histone acetyltransferase. Nature 384, 641–643 (1996).

    CAS  PubMed  Google Scholar 

  48. Ogryzko, V. V., Schiltz, R. L., Russanova, V., Howard, B. H. & Nakatani, Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87, 953–959 (1996).

    CAS  PubMed  Google Scholar 

  49. Spencer, T. E. et al. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 389, 194–198 (1997).

    CAS  PubMed  Google Scholar 

  50. Chen, H. et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90, 569–580 (1997).

    CAS  PubMed  Google Scholar 

  51. Horlein, A. J. et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377, 397–404 (1995).

    CAS  PubMed  Google Scholar 

  52. Chen, J. D. & Evans, R. M. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377, 454–457 (1995).

    CAS  PubMed  Google Scholar 

  53. Sande, S. & Privalsky, M. L. Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors. Mol. Endocrinol. 10, 813–825 (1996).

    CAS  PubMed  Google Scholar 

  54. Heinzel, T. et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387, 43–48 (1997).

    CAS  PubMed  Google Scholar 

  55. Nagy, L. et al. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89, 373–380 (1997).

    CAS  PubMed  Google Scholar 

  56. Koh, S. S., Chen, D., Lee, Y. H. & Stallcup, M. R. Synergistic enhancement of nuclear receptor function by p160 coactivators and two coactivators with protein methyltransferase activities. J. Biol. Chem. 276, 1089–1098 (2001).

    CAS  PubMed  Google Scholar 

  57. Chen, D. et al. Regulation of transcription by a protein methyltransferase. Science 284, 2174–2177 (1999).

    CAS  PubMed  Google Scholar 

  58. Stallcup, M. R. Role of protein methylation in chromatin remodeling and transcriptional regulation. Oncogene 20, 3014–3020 (2001).

    CAS  PubMed  Google Scholar 

  59. Torchia, J. et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387, 677–684 (1997).

    CAS  PubMed  Google Scholar 

  60. Heery, D. M., Kalkhoven, E., Hoare, S. & Parker, M. G. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733–736 (1997).

    CAS  PubMed  Google Scholar 

  61. Shiau, A. K. et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95, 927–937 (1998). References 59 and 60 describe how the L–X–X–L–L-containing peptide mediates co-activator recruitment to the LBD. Reference 61 describes the X-ray crystallographic structure of ER bound by oestrogens and anti-oestrogens. References 69–71 further show that a similar peptide in corepressors is responsible for their interaction with the LBD of nuclear receptors.

    CAS  PubMed  Google Scholar 

  62. Metzger, D., Berry, M., Ali, S. & Chambon, P. Effect of antagonists on DNA binding properties of the human estrogen receptor in vitro and in vivo. Mol. Endocrinol. 9, 579–591 (1995).

    CAS  PubMed  Google Scholar 

  63. Gibson, M. K. et al. The mechanism of ICI 164,384 antiestrogenicity involves rapid loss of estrogen receptor in uterine tissue. Endocrinology 129, 2000–2010 (1991).

    CAS  PubMed  Google Scholar 

  64. Dauvois, S., Danielian, P. S., White, R. & Parker, M. G. Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. Proc. Natl Acad. Sci. USA 89, 4037–4041 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lerner, L. J. & Jordan, V. C. Development of antiestrogens and their use in breast cancer: eighth Cain memorial award lecture. Cancer Res. 50, 4177–4189 (1990).

    CAS  PubMed  Google Scholar 

  66. Jordan, V. C., MacGregor, J. I. & Tonetti, D. A. Tamoxifen: from breast cancer therapy to the design of a postmenopausal prevention maintenance therapy. Clin. Oncol. 9, 390–394 (1997). | PubMed |

    CAS  Google Scholar 

  67. Cosman, F. & Lindsay, R. Selective estrogen receptor modulators: clinical spectrum. Endocr. Rev. 20, 418–434 (1999).

    CAS  PubMed  Google Scholar 

  68. Lavinsky, R. M. et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc. Natl Acad. Sci. USA 95, 2920–2925 (1998). Shows that downregulation of NCOR1 reduces the anti-oestrogenic activity of tamoxifen and might result in resistance.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Hu, X. & Lazar, M. A. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402, 93–96 (1999).

    CAS  PubMed  Google Scholar 

  70. Perissi, V. et al. Molecular determinants of nuclear receptor-corepressor interaction. Genes Dev. 13, 3198–3208 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Nagy, L. et al. Mechanism of corepressor binding and release from nuclear hormone receptors. Genes Dev. 13, 3209–3216 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kuukasjarvi, T., Kononen, J., Helin, H., Holli, K. & Isola, J. Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J. Clin. Oncol. 14, 2584–2589 (1996).

    CAS  PubMed  Google Scholar 

  73. Hopp, T. A. & Fuqua, S. A. Estrogen receptor variants. J. Mammary Gland Biol. Neoplasia 3, 73–83 (1998).

    CAS  PubMed  Google Scholar 

  74. Zhang, Q. X., Borg, A., Wolf, D. M., Oesterreich, S. & Fuqua, S. A. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 57, 1244–1249 (1997). Identifies a tyrosine 537-to-asparagine mutation in breast tumours that results in ligand-independent ER activity.

    CAS  PubMed  Google Scholar 

  75. Weis, K. E., Ekena, K., Thomas, J. A., Lazennec, G. & Katzenellenbogen, B. S. Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. Mol. Endocrinol. 10, 1388–1398 (1996).

    CAS  PubMed  Google Scholar 

  76. White, R., Sjoberg, M., Kalkhoven, E. & Parker, M. G. Ligand-independent activation of the oestrogen receptor by mutation of a conserved tyrosine. EMBO J. 16, 1427–1435 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Arnold, S. F., Obourn, J. D., Jaffe, H. & Notides, A. C. Phosphorylation of the human estrogen receptor on tyrosine 537 in vivo and by src family tyrosine kinases in vitro. Mol. Endocrinol. 9, 24–33 (1995).

    CAS  PubMed  Google Scholar 

  78. Wang, C. et al. Direct acetylation of the estrogen receptor-α hinge region by p300 regulates transactivation and hormone sensitivity. J. Biol. Chem. 276, 18375–18383 (2001).

    CAS  PubMed  Google Scholar 

  79. Fuqua, S. A. et al. A hypersensitive estrogen receptor-α mutation in premalignant breast lesions. Cancer Res. 60, 4026–4029 (2000).

    CAS  PubMed  Google Scholar 

  80. Roodi, N. et al. Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer. J. Natl Cancer Inst. 87, 446–451 (1995).

    CAS  PubMed  Google Scholar 

  81. Ignar-Trowbridge, D. M. et al. Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. Proc. Natl Acad. Sci. USA 89, 4658–4662 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Curtis, S. W. et al. Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc. Natl Acad. Sci. USA 93, 12626–12630 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Chen, D., Pace, P. E., Coombes, R. C. & Ali, S. Phosphorylation of human estrogen receptor-α by protein kinase A regulates dimerization. Mol. Cell. Biol. 19, 1002–1015 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Miller, W. R., Elton, R. A., Dixon, J. M., Chetty, U. & Watson, D. M. Cyclic AMP binding proteins and prognosis in breast cancer. Br. J. Cancer 61, 263–266 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Joel, P. B., Traish, A. M. & Lannigan, D. A. Estradiol-induced phosphorylation of serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase. J. Biol. Chem. 273, 13317–13323 (1998).

    CAS  PubMed  Google Scholar 

  86. Chen, D. et al. Activation of estrogen receptor-α by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7. Mol. Cell 6, 127–137 (2000).

    CAS  PubMed  Google Scholar 

  87. Kato, S. et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270, 1491–1494 (1995).

    CAS  PubMed  Google Scholar 

  88. Bunone, G., Briand, P. A., Miksicek, R. J. & Picard, D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 15, 2174–2183 (1996). References 87 and 88 show ER phosphorylation by ERK1/2, which results in ligand-independent activation of ER.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Joel, P. B. et al. pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Mol. Cell. Biol. 18, 1978–1984 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Coutts, A. S. & Murphy, L. C. Elevated mitogen-activated protein kinase activity in estrogen-nonresponsive human breast cancer cells. Cancer Res. 58, 4071–4074 (1998).

    CAS  PubMed  Google Scholar 

  91. Shim, W. S. et al. Estradiol hypersensitivity and mitogen-activated protein kinase expression in long-term estrogen deprived human breast cancer cells in vivo. Endocrinology 141, 396–405 (2000).

    CAS  PubMed  Google Scholar 

  92. Sivaraman, V. S., Wang, H., Nuovo, G. J. & Malbon, C. C. Hyperexpression of mitogen-activated protein kinase in human breast cancer. J. Clin. Invest. 99, 1478–1483 (1997). Describes overexpression and/or increased activity of ERK1/2 in breast cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Gee, J. M., Robertson, J. F., Ellis, I. O. & Nicholson, R. I. Phosphorylation of ERK1/2 mitogen-activated protein kinase is associated with poor response to anti-hormonal therapy and decreased patient survival in clinical breast cancer. Int. J. Cancer 95, 247–254 (2001). Describes a correlation between ERK1/2 activity and poor response to endocrine therapy in breast cancer.

    CAS  PubMed  Google Scholar 

  94. Benz, C. C. et al. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res. Treat. 24, 85–95 (1993).

    CAS  Google Scholar 

  95. Kurokawa, H. et al. Inhibition of HER2/neu (ERBB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res. 60, 5887–5894 (2000).

    CAS  PubMed  Google Scholar 

  96. Nicholson, R. I. et al. Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer. Endocr. Relat. Cancer 8, 175–182 (2001).

    CAS  PubMed  Google Scholar 

  97. Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999).

    CAS  PubMed  Google Scholar 

  98. Martin, M. B. et al. A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology 141, 4503–4511 (2000).

    CAS  PubMed  Google Scholar 

  99. Campbell, R. A. et al. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J. Biol. Chem. 276, 9817–9824 (2001).

    CAS  PubMed  Google Scholar 

  100. Testa, J. R. & Bellacosa, A. AKT plays a central role in tumorigenesis. Proc. Natl Acad. Sci. USA 98, 10983–10985 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science 275, 1943–1947 (1997).

    CAS  PubMed  Google Scholar 

  102. Gayther, S. A. et al. Mutations truncating the EP300 acetylase in human cancers. Nature Genet. 24, 300–303 (2000).

    CAS  PubMed  Google Scholar 

  103. Anzick, S. L. et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277, 965–968 (1997). Identified a gene that is frequently amplified in breast cancer as the p160 co-activator NCOA3 (AIB1).

    CAS  PubMed  Google Scholar 

  104. Bautista, S. et al. In breast cancer, amplification of the steroid receptor coactivator gene AIB1 is correlated with estrogen and progesterone receptor positivity. Clin. Cancer Res. 4, 2925–2929 (1998). Correlates NCOA3 expression with ER and progesterone receptor status.

    CAS  PubMed  Google Scholar 

  105. Smith, C. L., Nawaz, Z. & OqMalley, B. W. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol. Endocrinol. 11, 657–666 (1997).

    CAS  PubMed  Google Scholar 

  106. Webb, P. et al. Estrogen receptor activation function 1 works by binding p160 coactivator proteins. Mol. Endocrinol. 12, 1605–1618 (1998).

    CAS  PubMed  Google Scholar 

  107. Lau, O. D. et al. HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol. Cell 5, 589–595 (2000).

    CAS  PubMed  Google Scholar 

  108. Turlais, F. et al. High-throughput screening for identification of small molecule inhibitors of histone acetyltransferases using scintillating microplates (flashplate). Anal. Biochem. 298, 62–68 (2001).

    CAS  PubMed  Google Scholar 

  109. Chan, C. M., Lykkesfeldt, A. E., Parker, M. G. & Dowsett, M. Expression of nuclear receptor interacting proteins TIF-1, SUG-1, receptor interacting protein 140, and corepressor SMRT in tamoxifen-resistant breast cancer. Clin. Cancer Res. 5, 3460–3467 (1999).

    CAS  PubMed  Google Scholar 

  110. Vigushin, D. M. et al. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin. Cancer Res. 7, 971–976 (2001).

    CAS  PubMed  Google Scholar 

  111. Cohen, L. A. et al. Chemoprevention of carcinogen-induced mammary tumorigenesis by the hybrid polar cytodifferentiation agent, suberanilohydroxamic acid (SAHA). Anticancer Res. 19, 4999–5005 (1999).

    CAS  PubMed  Google Scholar 

  112. Marks, P. A., Rifkind, R. A., Richon, V. M. & Breslow, R. Inhibitors of histone deacetylase are potentially effective anticancer agents. Clin. Cancer Res. 7, 759–760 (2001).

    CAS  PubMed  Google Scholar 

  113. Zwijsen, R. M. et al. CDK-independent activation of estrogen receptor by cyclin D1. Cell 88, 405–415 (1997).

    CAS  PubMed  Google Scholar 

  114. Neuman, E. et al. Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of CDK4. Mol. Cell. Biol. 17, 5338–5347 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang, T. C. et al. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369, 669–671 (1994).

    CAS  PubMed  Google Scholar 

  116. Fantl, V., Stamp, G., Andrews, A., Rosewell, I. & Dickson, C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 9, 2364–2372 (1995).

    CAS  PubMed  Google Scholar 

  117. Sicinski, P. et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82, 621–630 (1995).

    CAS  PubMed  Google Scholar 

  118. Zwijsen, R. M., Buckle, R. S., Hijmans, E. M., Loomans, C. J. & Bernards, R. Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Genes Dev. 12, 3488–3498 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. McMahon, C., Suthiphongchai, T., DiRenzo, J. & Ewen, M. E. P/CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor. Proc. Natl Acad. Sci. USA 96, 5382–5387 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Peto, R., Boreham, J., Clarke, M., Davies, C. & Beral, V. UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years. Lancet 355, 1822–1823 (2000).

    CAS  PubMed  Google Scholar 

  121. Lakhani, S. R. & Ashworth, A. Microarray and histopathological analysis of tumours: the future and the past? Nature Rev. Cancer 1, 151–157 (2001).

    CAS  Google Scholar 

  122. Halberstaeder, I. & Hochsman, A. The artificial menopause and cancer of the breast. J. Am. Med. Assoc. 131, 810–816 (1946).

    Google Scholar 

  123. Boyd, S. On oophorectomy in cancer of the breast. Br. Med. J. 2, 1161–1167 (1900).

    Google Scholar 

  124. Lathrop, A. E. C. & Loeb, L. Further investigations on the origins of tumors in mice. III. On the part played by internal secretions in the spontaneous development of tumors. J. Cancer Res. 1, 1–16 (1916).

    CAS  PubMed  Google Scholar 

  125. Allen, E. & Doisy, E. A. An ovarian hormone: preliminary report on its localization, extraction and partial purification and action in test animals. J. Am. Med. Assoc. 81, 819–821 (1923).

    CAS  Google Scholar 

  126. Lacassagne, A. Hormonal pathogenesis of adenocarcinoma of the breast. Am. J. Cancer 27, 217–225 (1936). The first paper to raise the possibility that breast cancer could be prevented by the use of oestrogen antagonists.

    Google Scholar 

  127. Lerner, L. J., Holthaus, J. F. & Thompson, C.R. A nonsteroidal estrogen antagonist 1-(p-2-diethylaminoethoxyphenyl)-1-phenyl-2-p-methoxyphenyl-ethanol. Endocrinology 63, 295–318 (1958).

    CAS  PubMed  Google Scholar 

  128. Lerner, L. J. in Non-steroidal Anti-oestrogens: Molecular Pharmacology and Antitumour Activity (eds Sutherland, R. L. & Jordan, V. C.) 1–6 (Sydney Academic Press, Sydney, 1981).

    Google Scholar 

  129. Jensen, E. V. & Jacobon, H. I. Basic guides to the mechanism of estrogen action. Recent Prog. Horm. Res. 18, 387–414 (1962).

    CAS  Google Scholar 

  130. Toft, D. & Gorski, J. A receptor molecule for estrogens: isolation from the rat uterus and preliminary characterization. Proc. Natl Acad. Sci. USA 55, 1574–1581 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Gorski, J., Toft, D., Shyamala, G., Smith, D. & Notides, A. Hormone receptors: studies on the interaction of estrogen with the uterus. Recent Prog. Horm. Res. 24, 45–80 (1968).

    CAS  PubMed  Google Scholar 

  132. Jensen, E. V. et al. A two-step mechanism for the interaction of estradiol with rat uterus. Proc. Natl Acad. Sci. USA 59, 632–638 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Green, S. et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 320, 134–139 (1986).

    CAS  PubMed  Google Scholar 

  134. Harper, M. J. & Walpole, A. L. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature 212, 87 (1966).

  135. Fisher, B. et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90, 1371–1388 (1998).

    CAS  PubMed  Google Scholar 

  136. Veronesi, U. et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 352, 93–97 (1998).

    CAS  PubMed  Google Scholar 

  137. Powles, T. et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital Tamoxifen Randomised Chemoprevention Trial. Lancet 352, 98–101 (1998).

    CAS  PubMed  Google Scholar 

  138. Cummings, S. R. et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. J. Am. Med. Assoc. 281, 2189–2197 (1999).

    CAS  Google Scholar 

  139. Kuiper, G. G., Enmark, E., Pelto-Huikko, M., Nilsson, S. & Gustafsson, J. A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl Acad. Sci. USA 93, 5925–5930 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Mosselman, S., Polman, J. & Dijkema, R. ERβ: identification and characterization of a novel human estrogen receptor. FEBS Lett. 392, 49–53 (1996).

    CAS  PubMed  Google Scholar 

  141. Dotzlaw, H., Leygue, E., Watson, P. H. & Murphy, L. C. Estrogen receptor-β messenger RNA expression in human breast tumor biopsies: relationship to steroid receptor status and regulation by progestins. Cancer Res. 59, 529–532 (1999).

    CAS  PubMed  Google Scholar 

  142. Jarvinen, T. A., Pelto-Huikko, M., Holli, K. & Isola, J. Estrogen receptor-β is coexpressed with ERα and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am. J. Pathol. 156, 29–35 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Mann, S. et al. Estrogen receptor-β expression in invasive breast cancer. Hum. Pathol. 32, 113–118 (2001).

    CAS  PubMed  Google Scholar 

  144. Roger, P. et al. Decreased expression of estrogen receptor-β protein in proliferative preinvasive mammary tumors. Cancer Res. 61, 2537–2541 (2001).

    CAS  PubMed  Google Scholar 

  145. Ogawa, S. et al. Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor of estrogen action in human. Nucleic Acids Res. 26, 3505–3012 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Saji, S. J. E., Nilsson, S., Rylander, T., Warner, M. & Gustafsson, J. A. Estrogen receptors-α and -β in the rodent mammary gland. Proc. Natl Acad. Sci. USA 97, 337–342 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Sun, J. et al. Novel ligands that function as selective estrogens or antiestrogens for estrogen receptor-α or estrogen receptor-β. Endocrinology 140, 800–804 (1999).

    CAS  PubMed  Google Scholar 

  148. Meyers, M. J., Sun, J., Carlson, K. E., Katzenellenbogen, B. S. & Katzenellenbogen, J. A. Estrogen receptor subtype-selective ligands: asymmetric synthesis and biological evaluation of cis- and trans-5,11-dialkyl-5,6,11,12-tetrahydrochrysenes. J. Med. Chem. 42, 2456–2468 (1999).

    CAS  PubMed  Google Scholar 

  149. Howe, L. R., Subbaramaiah, K., Brown, A. M. & Dannenberg, A. J. Cyclooxygenase-2: a target for the prevention and treatment of breast cancer. Endocr. Relat. Cancer 8, 97–114 (2001).

    CAS  PubMed  Google Scholar 

  150. Lange, C. A., Richer, J. K. & Horwitz, K. B. Hypothesis: progesterone primes breast cancer cells for cross-talk with proliferative or antiproliferative signals. Mol. Endocrinol. 13, 829–836 (1999).

    CAS  PubMed  Google Scholar 

  151. Shao, D. & Lazar, M. A. Modulating nuclear receptor function: may the phos be with you. J. Clin. Invest. 103, 1617–1618 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Migliaccio, A. et al. Tyrosine kinase/p21RAS/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J. 15, 1292–1300 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Castoria, G. et al. Non-transcriptional action of oestradiol and progestin triggers DNA synthesis. EMBO J. 18, 2500–2510 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Kousteni, S. et al. Nongenotropic, sex-nonspecific signalling through the estrogen or androgen receptors: dissocation from transcriptional activity. Cell 104, 719–730 (2001).

    CAS  PubMed  Google Scholar 

  155. Simoncini, T. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Castoria, G. et al. PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. EMBO J. 20, 6050–6059 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Paech, K. et al. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277, 1508–1510 (1997).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Buluwela and C. Palmieri for helpful discussions and M. Slade for ER staining slides. We also thank G. Greene for ER LBD structures. We apologize to those whose work could not be cited due to space constraints.

Author information

Authors and Affiliations

  1. Department of Cancer Medicine and Cancer Research Campaign Laboratories, Faculty of Medicine, Imperial College of Science, Technology & Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Simak Ali & R. Charles Coombes

  2. Simak Ali & R. Charles Coombes

Authors
  1. Simak Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Charles Coombes
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

CancerNet:

breast cancer

glioblastoma

prostate cancer

 LocusLink:

AKT

aromatase

casein kinase II

catechol O-methyltransferase

CBP

CDK2

CDK4

CDK6

CDK7

cyclin D1

cyclin E

COX-2

EGF

EGFR

ERα

ERβ

ERBB2

ERK1

ERK2

GRB2

HDACs

heregulin

IGF-1

IL-6

LHRH

NCOA1

NCOA2

NCOA3

NCOR1

NCOR2

oncostatin M

p300

PCAF

PI3K

progesterone receptor

protein kinase A

PTEN

RAF

RAS

RSK

TFIIH

TRAP

 Medscape DrugInfo:

goserelin

Herceptin

raloxifene

tamoxifen

FURTHER INFORMATION

Breast Cancer Information Core

Nature Medicine special focus on breast cancer

NIH Biology of the Mammary Gland

Glossary

INVOLUTION

Restoration of the normal size of an organ.

END BUD

Epithelial structures from which the milk-producing alveoli of the mammary gland develop during pregnancy.

MESENCHYME

Embryonic tissue composed of loosely organized, unpolarized cells of both mesodermal and ectodermal (for example, neural crest) origin, with a proteoglycan-rich extracellular matrix.

OSTEOBLASTS

Cells that reside in bone, where they are responsible for depositing the bone matrix.

CHONDROCYTES

Cells that produce cartilage.

CYTOCHROME P450 ENZYME COMPLEX

Haem-containing enzymes that oxidize small molecules, including many carcinogens.

ADJUVANT THERAPY

Therapy given in addition to the primary form of treatment — for example, after surgery.

MICROMETASTASES

Clinically undetectable secondary tumours.

ZINC FINGER

A protein module in which conserved cysteine or histidine residues coordinate a zinc atom. Some zinc-finger regions bind specific DNA sequences; others are involved in protein–protein interactions.

GENERAL TRANSCRIPTION MACHINERY

A set of protein complexes, including RNA polymerase II, that are absolutely required for the initiation of mRNA synthesis and that are sufficient for low-level initiation of mRNA synthesis, at least in vitro.

HISTONE ACETYLTRANSFERASE

An enzyme that catalyses the addition of acetyl groups to lysine residues on the amino-terminal tails of histones. Histone acetylation leads to chromatin decondensation and increased rates of transcriptional initiation.

HISTONE DEACETYLASE

An enzyme that catalyses the removal of acetyl groups from lysine residues on the amino-terminal tails of histones. Histone deacetylation leads to chromatin condensation and decreased rates of transcriptional initiation.

BASAL TRANSCRIPTION FACTORS

A set of protein complexes that associate with RNA polymerase II during the initiation of all mRNA synthesis. Sometimes called general transcription factors.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ali, S., Coombes, R. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2, 101–112 (2002). https://doi.org/10.1038/nrc721

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc721

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing