Advertisement

The Dark Side of Antihormonal Action in Breast Cancer

  • Julia M.W. Gee
  • Andrew Stone
  • Richard A. McClelland
  • Stephen Hiscox
  • Iain R. Hutcheson
  • Nicola J. Jordan
  • Heidi M. Fiegl
  • Martin Widschwendter
  • Victoria E. Shaw
  • Denise Barrow
  • Robert I. Nicholson

Abstract

Antihormones are of substantial benefit in treating oestrogen receptor-α positive (ER+) breast cancer. However, their anti-tumour effect is limited by emergence of resistance. Our in vitro studies are highlighting a new underlying concept: that antihormones are not passive bystanders but alongside growth inhibitory effects promote adverse compensatory mechanisms within tumour cells. These mechanisms involve drug-induction of signalling elements normally suppressed by oestrogen (E2)-occupied E R˜ While best exemplified by the tyrosine kinases epidermal growth factor receptor and HER2, microarrays reveal the true diversity of the induced signalling kinases, where their potential to promote resistance is exacerbated under paracrine conditions. Such drug-induced events permit initial ER+ breast cancer cell survival, allow development and maintenance of resistance, and also promote gain of invasiveness under conditions of poor intercellular contact. In addition, prolonged antihormonal exposure is associated with epigenetic silencing of classical E2-induced tumour suppressors, an event which further contributes to resistance. Based on proof of principle experiments targeting induced signalling events alongside antihormones or restoring E2-induced suppressor genes through DNA methylation inhibitor-containing strategies, it is our belief that continued deciphering of these mechanisms will reveal improved treatments for breast cancer.

Keywords

Antihormone Resistance Microarray Compensatory signalling Tumour suppressor 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Agrawal A, Gutteridge E, Gee JM, Nicholson RI, Robertson JF (2005) Overview of tyrosine kinase inhibitors in clinical breast cancer. Endocr Relat Cancer 12:S135–S144.PubMedCrossRefGoogle Scholar
  2. Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L, De Placido S, Osborne CK, Schiff R (2007) Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multi-agent HER-targeted therapy. J Natl Cancer Inst 99:694–705.PubMedCrossRefGoogle Scholar
  3. Arpino G, Wiechmann L, Osborne CK, Schiff R (2008) Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev 29:217–233.PubMedCrossRefGoogle Scholar
  4. Badia E, Duchesne MJ, Semlali A, Fuentes M, Giamarchi C, Richard-Foy H, Nicolas JC, Pons M (2000) Long-term hydroxytamoxifen treatment of an MCF-7-derived breast cancer cell line irreversibly inhibits the expression of estrogenic genes through chromatin remodeling. Cancer Res 60:4130–4138.PubMedGoogle Scholar
  5. Bates NP, Hurst HC (1997) An intron 1 enhancer element mediates oestrogen-induced suppression of ERBB2 expression. Oncogene 15:473–481.PubMedCrossRefGoogle Scholar
  6. Bates RC, Edwards NS, Burns GF, Fisher DE (2001) A CD44 survival pathway triggers chemoresistance via lyn kinase and phosphoinositide 3-kinase/akt in colon carcinoma cells. Cancer Res 61:5275–5283.PubMedGoogle Scholar
  7. Borley AC, Barrett-Lee PJ, Gee JMW, Shaw V, Nicholson RI, Hiscox SE (2007) Anti-estrogens promote an invasive phenotype in intercellular adhesion deficient breast cancer cells. Breast Cancer Res Treat 106:S1, 24.Google Scholar
  8. Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small g proteins. Cell 129:865–877.PubMedCrossRefGoogle Scholar
  9. Britton DJ, Hutcheson IR, Knowlden JM, Barrow D, Giles M, McClelland RA, Gee JM, Nicholson RI (2006) Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat 96:131–146.PubMedCrossRefGoogle Scholar
  10. Cheng AS, Culhane AC, Chan MW, Venkataramu CR, Ehrich M, Nasir A, Rodriguez BA, Liu J, Yan PS, Quackenbush J, Nephew KP, Yeatman TJ, Huang TH (2008) Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. Cancer Res 68:1786–1796.PubMedCrossRefGoogle Scholar
  11. Cheung KL, Willsher PC, Pinder SE, Ellis IO, Elston CW, Nicholson RI, Blamey RW, Robertson JF (1997) Predictors of response to second-line endocrine therapy for breast cancer. Breast Cancer Res Treat 45:219–224.PubMedCrossRefGoogle Scholar
  12. Chia S, Gradishar W (2008) Fulvestrant: expanding the endocrine treatment options for patients with hormone receptor-positive advanced breast cancer. Breast 17:S16–S21.PubMedCrossRefGoogle Scholar
  13. Cunliffe HE, Ringner M, Bilke S, Walker RL, Cheung JM, Chen Y, Meltzer PS (2003) The gene expression response of breast cancer to growth regulators: patterns and correlation with tumour expression profiles. Cancer Res 63:7158–7166.PubMedGoogle Scholar
  14. Demirpence E, Semlali A, Oliva J, Balaguer P, Badia E, Duchesne MJ, Nicolas JC, Pons M (2002) An estrogen-responsive element-targeted histone deacetylase enzyme has an antiestrogen activity that differs from that of hydroxytamoxifen. Cancer Res 62:6519–6528.PubMedGoogle Scholar
  15. Droufakou S, Deshmane V, Roylance R, Hanby A, Tomlinson I, Hart IR (2001) Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast. Int J Cancer 92:404–408.PubMedCrossRefGoogle Scholar
  16. Dunn M, Sinha P, Campbell R, Blackburn E, Levinson N, Rampaul R, Bates T, Humphreys S, Gullick WJ (2004) Co-expression of neuregulins 1, 2, 3 and 4 in human breast cancer. J Pathol 203:672–680.PubMedCrossRefGoogle Scholar
  17. Fan M, Yan PS, Hartman-Frey C, Chen L, Paik H, Oyer SL, Salisbury JD, Cheng AS, Li L, Abbosh PH, Huang TH, Nephew KP (2006) Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res 66:11954–11966.PubMedCrossRefGoogle Scholar
  18. Fan P, Wang J, Santen RJ, Yue W (2007) Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha Out Of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. Cancer Res 67:1352–1360.PubMedCrossRefGoogle Scholar
  19. Fersis N, Smyczek-Gargya B, Armeanu S, Gagulic E, Pantic L, Relakis K, Friedrich M, Wallwiener D (2004) Changes in vascular endothelial growth factor (VEGF) after chemoendocrine therapy in breast cancer. Eur J Gynaecol Oncol 25:45–50.PubMedGoogle Scholar
  20. Finetti P, Cervera N, Charafe-Jauffret E, Chabannon C, Charpin C, Chaffanet M, Jacquemier J, Viens P, Birnbaum D, Bertucci F (2008) Sixteen-kinase gene expression identifies luminal breast cancers with poor prognosis. Cancer Res 68:767–776.PubMedCrossRefGoogle Scholar
  21. Fox BP, Kandpal RP (2004) Invasiveness of breast carcinoma cells and transcript profile: eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem Biophys Res Commun 318:882–892.PubMedCrossRefGoogle Scholar
  22. Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS (2003) Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 144:4562–4574.PubMedCrossRefGoogle Scholar
  23. Frasor J, Stossi F, Danes JM, Komm B, Lyttle CR, Katzenellenbogen BS (2004) Selective estrogen receptor modulators: discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells. Cancer Res 64:1522–1533.PubMedCrossRefGoogle Scholar
  24. Gee JM, Hutcheson IR (2005) Understanding endocrine resistance: the critical need for sequential samples from clinical breast cancer and novel in vitro models. Breast Cancer Res Treat 7:187–189.Google Scholar
  25. Gee JM, Willsher PC, Kenny FS, Robertson JF, Pinder SE, Ellis IO, Nicholson RI (1999) Endocrine response and resistance in breast cancer: a role for the transcription factor fos. Int J Cancer 84:54–61.PubMedCrossRefGoogle Scholar
  26. Gee JM, Harper ME, Hutcheson IR, Madden TA, Barrow D, Knowlden JM, McClelland RA, Jordan N, Wakeling AE, Nicholson RI (2003) The anti-epidermal growth factor receptor agent gefitinib (ZD1839/iressa) improves anti-hormone response and prevents development of resistance in breast cancer in vitro. Endocrinology 144:5105–5117.PubMedCrossRefGoogle Scholar
  27. Gee J, Shaw V, Burmi R, McClelland R, Morgan H, Harper M, Hiscox S, Barrow D, Lewis P, Nicholson R (2004) Array profiling of survival and resistance genes in anti-hormone-treated breast cancer cells. Intl J Mol Med 14:S81.Google Scholar
  28. Gee JM, Robertson JF, Gutteridge E, Ellis IO, Pinder SE, Rubini M, Nicholson RI (2005a) Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. Endocr Relat Cancer 12:S99–S111.CrossRefGoogle Scholar
  29. Gee JM, Howell A, Gullick WJ, Benz CC, Sutherland RL, Santen RJ, Martin LA, Ciardiello F, Miller WR, Dowsett M, Barrett-Lee P, Robertson JF, Johnston Jones SRHE, Wakeling AE, Duncan R, Nicholson RI (2005b) Consensus statement. Workshop on therapeutic resistance in breast cancer: impact of growth factor signalling pathways and implications for future treatment. Endocr Relat Cancer 12:S1–S7.CrossRefGoogle Scholar
  30. Gee JM, Shaw VE, Hiscox SE, McClelland RA, Rushmere NK, Nicholson RI (2006) Deciphering antihormone-induced compensatory mechanisms in breast cancer and their therapeutic implications. Endocr Relat Cancer 13:S77–S88.PubMedCrossRefGoogle Scholar
  31. Goldenberg-Furmanov M, Stein I, Pikarsky E, Rubin H, Kasem S, Wygoda M, Weinstein I, Reuveni H, Ben-Sasson SA (2004) Lyn is a target gene for prostate cancer: sequence-based inhibition induces regression of human tumour xenografts. Cancer Res 64:1058–1066.PubMedCrossRefGoogle Scholar
  32. Guasch RM, Scambler P, Jones GE, Ridley AJ (1998) RhoE regulates actin cytoskeleton organization and cell migration. Mol Cell Biol 18:4761–4771.PubMedGoogle Scholar
  33. Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, Allred DC, Schiff R, Osborne CK, Dowsett M (2005) Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23:2469–2476.PubMedCrossRefGoogle Scholar
  34. Harper ME, Smith C, Nicholson RI (2005) Upregulation of CD44s and variants in anti-hormone resistant breast cancer cells. Eur J Cancer 3:A71.Google Scholar
  35. Higgins KJ, Liu S, Abdelrahim M, Vanderlaag K, Liu X, Porter W, Metz R, Safe S (2008) Vascular endothelial growth factor receptor-2 expression is down-regulated by 17beta-estradiol in MCF-7 breast cancer cells by estrogen receptor alpha/sp proteins. Mol Endocrinol 22:388–402.PubMedCrossRefGoogle Scholar
  36. Hiscox S, Morgan L, Barrow D, Dutkowski C, Wakeling A, Nicholson RI (2004) Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile & invasive phenotype: inhibition by gefitinib (“iressa”, ZD1839). Clin Exp Metastasis 21:201–212.PubMedCrossRefGoogle Scholar
  37. Hiscox S, Jiang WG, Obermeier K, Taylor K, Morgan L, Burmi R, Barrow D, Nicholson RI (2006a) Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation. Int J Cancer 118:290–301.CrossRefGoogle Scholar
  38. Hiscox S, Jordan NJ, Jiang W, Harper M, McClelland R, Smith C, Nicholson RI (2006b) Chronic exposure to fulvestrant promotes overexpression of the c-met receptor in breast cancer cells: implications for tumour-stroma interactions. Endocr Relat Cancer 13:1085–1099.CrossRefGoogle Scholar
  39. Hiscox S, Borley A, Barratt-Lee P, Jordan NJ, Gee J, Shaw V, McClelland R, Nicholson RI (2006c) Tamoxifen promotes cellular invasion in intercellular-adhesion deficient breast cancer cells. J Steroid Biochem Mol Biol 76(1–5):154.Google Scholar
  40. Hiscox S, Morgan L, Green TP, Barrow D, Gee J, Nicholson RI (2006d) Elevated src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Res Treat 97:263–274.CrossRefGoogle Scholar
  41. Hiscox S, Green TP, Smith C, James M, Jordan N, Nicholson RI (2007) Combination therapy with AZD0530 and tamoxifen prevents acquired anti-oestrogen resistance in breast cancer cells. Proc Am Assoc Can Res Molecular Targets and Cancer Therapeutics Meeting A231.Google Scholar
  42. Hodges LC, Cook JD, Lobenhofer EK, Li L, Bennett L, Bushel PR, Aldaz CM, Afshari CA, Walker CL (2003) Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes in breast cancer cells. Mol Cancer Res 1:300–311.PubMedGoogle Scholar
  43. Holloway JN, Murthy S, El-Ashry D (2004) A cytoplasmic substrate of mitogen-activated protein kinase is responsible for estrogen receptor-alpha down-regulation in breast cancer cells: the role of nuclear factor-kappa b. Mol Endocrinol 18:1396–1410.PubMedCrossRefGoogle Scholar
  44. Howell A (2006) Fulvestrant (“faslodex”): current and future role in breast cancer management. Crit Rev Oncol Hematol 57:265–273.PubMedCrossRefGoogle Scholar
  45. Hutcheson IR, Knowlden JM, Hiscox SE, Barrow D, Gee JM, Robertson JF, Ellis IO, Nicholson RI (2007) Heregulin beta1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells. Breast Cancer Res 9:R50.PubMedCrossRefGoogle Scholar
  46. Inoue A, Yoshida N, Omoto Y, Oguchi S, Yamori T, Kiyama R, Hayashi S (2002) Development of cDNA microarray for expression profiling of estrogen-responsive genes. J Mol Endocrinology 29:175–192.CrossRefGoogle Scholar
  47. Johnston SR, Leary A, Martin LA, Smith IE, Dowsett M (2008) Enhancing endocrine response with novel targeted therapies: why have the clinical trials to date failed to deliver on the preclinical promise? Cancer 112:710–717.PubMedCrossRefGoogle Scholar
  48. Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167.PubMedCrossRefGoogle Scholar
  49. Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI (2004) Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 11:793–814.PubMedCrossRefGoogle Scholar
  50. Kaipparettu BA, Malik S, Konduri SD, Liu W, Rokavec M, van der Kuip H, Hoppe R, Hammerich-Hille S, Fritz P, Schroth W, Abele I, Das GM, Oesterreich S, Brauch H (2008) Estrogen-mediated downregulation of CD24 in breast cancer cells. Int J Cancer 123:66–72.PubMedCrossRefGoogle Scholar
  51. Kalaitzidis D, Gilmore TD (2005) Transcription factor cross-talk: the estrogen receptor and NF-kappaB. Trends Endocrinol Metab 16:46–52.PubMedCrossRefGoogle Scholar
  52. Kenny FS, Willsher PC, Gee JM, Nicholson R, Pinder SE, Ellis IO, Robertson JF (2001) Change in expression of ER, bcl-2 and MIB1 on primary tamoxifen and relation to response in ER positive breast cancer. Breast Cancer Res Treat 65:135–144.PubMedCrossRefGoogle Scholar
  53. Klein RM, Spofford LS, Abel EV, Ortiz A, Aplin AE (2008) B-RAF regulation of rnd3 participates in actin cytoskeletal and focal adhesion organization. Mol Biol Cell 19:498–508.PubMedCrossRefGoogle Scholar
  54. Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE, Nicholson RI (2003) Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 144:1032–1044.PubMedCrossRefGoogle Scholar
  55. Knowlden JM, Hutcheson IR, Barrow D, Gee JM, Nicholson RI (2005) Insulin-like growth factor-i receptor signalling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. Endocrinology 146:4609–4618.PubMedCrossRefGoogle Scholar
  56. Lavinsky RM, Jepsen K, Heinzel T, Torchia J, Mullen TM, Schiff R, Del-Rio AL, Ricote M, Ngo S, Gemsch J, Hilsenbeck SG, Osborne CK, Glass CK, Rosenfeld MG, Rose DW (1998) Diverse signalling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci U S A 95:2920–2925.PubMedCrossRefGoogle Scholar
  57. Levenson AS, Kliakhandler IL, Svoboda KM, Pease KM, Kaiser SA, Ward JE 3rd, Jordan VC (2002a) Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor alpha. Br J Cancer 87:449–456.CrossRefGoogle Scholar
  58. Levenson AS, Svoboda KM, Pease KM, Kaiser SA, Chen B, Simons LA, Jovanovic BD, Dyck PA, Jordan VC (2002b) Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor. Cancer Res 62:4419–4426.Google Scholar
  59. Leu YW, Yan PS, Fan M, Jin VX, Liu JC, Curran EM, Welshons WV, Wei SH, Davuluri RV, Plass C, Nephew KP, Huang TH (2004) Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer. Cancer Res 64:8184–8192.PubMedCrossRefGoogle Scholar
  60. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934.PubMedCrossRefGoogle Scholar
  61. Maynadier M, Nirdé P, Ramirez JM, Cathiard AM, Platet N, Chambon M, Garcia M (2008) Role of estrogens and their receptors in adhesion and invasiveness of breast cancer cells. Adv Exp Med Biol 617:485–491.PubMedCrossRefGoogle Scholar
  62. McClelland RA, Barrow D, Madden TA, Dutkowski CM, Pamment J, Knowlden JM, Gee JM, Nicholson RI (2001) Enhanced epidermal growth factor receptor signalling in MCF-7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (faslodex). Endocrinology 142:2776–2788.PubMedCrossRefGoogle Scholar
  63. McKeage K, Perry CM (2002) Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs 62:209–243.PubMedCrossRefGoogle Scholar
  64. Miller WR, Larionov A, Anderson TJ, Walker JR, Krause A, Evans DB, Dixon JM (2008) Predicting response and resistance to endocrine therapy: profiling patients on aromatase inhibitors. Cancer 112:689–694.PubMedCrossRefGoogle Scholar
  65. Miyamoto K, Ushijima T (2005) Diagnostic and therapeutic applications of epigenetics. Jpn J Clin Oncol 35:293–301.PubMedCrossRefGoogle Scholar
  66. Munzone E, Curigliano G, Rocca A, Bonizzi G, Renne G, Goldhirsch A, Nolè F (2006) Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy. Breast Cancer Res 8:R4.PubMedCrossRefGoogle Scholar
  67. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ (2006) Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 3:269–280.PubMedCrossRefGoogle Scholar
  68. Newman SP, Bates NP, Vernimmen D, Parker MG, Hurst HC (2000) Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer. Oncogene 19:490–497.PubMedCrossRefGoogle Scholar
  69. Nicholson RI, Johnston SR (2005) Endocrine therapy – current benefits and limitations. Breast Cancer Res Treat 93:S3–S10.PubMedCrossRefGoogle Scholar
  70. Nicholson RI, Staka C, Boyns F, Hutcheson IR, Gee JM (2004) Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy. Endocr Relat Cancer 11:623–641.PubMedCrossRefGoogle Scholar
  71. Nicholson RI, Hutcheson IR, Hiscox SE, Knowlden JM, Giles M, Barrow D, Gee JM (2005) Growth factor signalling and resistance to selective oestrogen receptor modulators and pure anti-oestrogens: the use of anti-growth factor therapies to treat or delay endocrine resistance in breast cancer. Endocr Relat Cancer 12:S29–S36.PubMedCrossRefGoogle Scholar
  72. Nicholson RI, Hutcheson IR, Jones HE, Hiscox SE, Giles M, Taylor KM, Gee JM (2007) Growth factor signalling in endocrine and anti-growth factor resistant breast cancer. Rev Endocr Metab Disord 8:241–253.PubMedCrossRefGoogle Scholar
  73. Normanno N, Di Maio M, De Maio E, De Luca A, de Matteis A, Giordano A, Perrone F, NCI-Naple Breast Cancer Group (2005) Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. Endocr Relat Cancer 12:721–747.Google Scholar
  74. Oliva J, El Messaoudi S, Pellestor F, Fuentes M, Georget V, Balaguer P, Cavaillès V, Vignon F, Badia E (2005) Involvement of HP1alpha protein in irreversible transcriptional inactivation by antiestrogens in breast cancer cells. FEBS Lett 579:4278–4286.PubMedCrossRefGoogle Scholar
  75. Platet N, Cunat S, Chalbos D, Rochefort H, Garcia M (2000) Unliganded and liganded estrogen receptors protect against cancer invasion via different mechanisms. Molecular Endocrinol 14:999–1009.CrossRefGoogle Scholar
  76. Platet N, Cathiard AM, Gleizes M, Garcia M (2004) Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Critical Reviews Oncol/Hematol 51:55–67.CrossRefGoogle Scholar
  77. Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45.PubMedCrossRefGoogle Scholar
  78. Powers MV, Workman P (2006) Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr Relat Cancer 13:S125–S135.PubMedCrossRefGoogle Scholar
  79. Pratt MA, Bishop TE, White D, Yasvinski G, Menard M, Niu MY, Clarke R (2003) Estrogen withdrawal-induced NF-kappaB activity and bcl-3 expression in breast cancer cells: roles in growth and hormone independence. Mol Cell Biol 23:6887–6900.PubMedCrossRefGoogle Scholar
  80. Rajendran RR, Nye AC, Frasor J, Balsara RD, Martini PG, Katzenellenbogen BS (2003) Regulation of nuclear receptor transcriptional activity by a novel DEAD box RNA helicase (DP97). J Biol Chem 278:4628–4638.PubMedCrossRefGoogle Scholar
  81. Rakha EA, Abd El Rehim D, Pinder SE, Lewis SA, Ellis IO (2005) E-cadherin expression in invasive non-lobular carcinoma of the breast and its prognostic significance. Histopathology 46:685–693.PubMedCrossRefGoogle Scholar
  82. Rakha EA, El-Sayed ME, Powe DG, Green AR, Habashy H, Grainge MJ, Robertson JF, Blamey R, Gee J, Nicholson RI, Lee AH, Ellis IO (2008) Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes. Eur J Cancer 44:73–83.PubMedCrossRefGoogle Scholar
  83. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6:1–6.PubMedGoogle Scholar
  84. Riento K, Villalonga P, Garg R, Ridley A (2005) Function and regulation of RhoE. Biochem Soc Trans 33:649–651.PubMedCrossRefGoogle Scholar
  85. Riggins RB, Zwart A, Nehra R, Clarke R (2005) The nuclear factor kappa b inhibitor parthenolide restores ICI 182,780 (faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells. Mol Cancer Ther 4:33–41.PubMedGoogle Scholar
  86. Shaw VE, Gee JMW, McClelland RA, Morgan H, Rushmere N, Nicholson RI (2005) Identification of anti-hormone induced genes as potential therapeutic targets in breast cancer. Proc Amer Assoc Cancer Res 46:A3706.Google Scholar
  87. Shou J, Massaraweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96:926–935.PubMedCrossRefGoogle Scholar
  88. Staka CM, Nicholson RI, Gee JM (2005) Acquired resistance to oestrogen deprivation: role for growth factor signalling kinases/oestrogen receptor cross-talk revealed in new MCF-7x model. Endocr Relat Cancer 12:S85–S97.PubMedCrossRefGoogle Scholar
  89. Stein B, Yang MX (1995) Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa b and C/EBP beta. Mol Cell Biol 15:4971–4979.PubMedGoogle Scholar
  90. Stone A, Jones H, Giles M, Gee J, Nicholson R (2008) Anti-oestrogen therapy switches off tumour suppressors and proapoptotic genes in breast cancer and reveals a new therapeutic opportunity. Breast Cancer Res 10:P41.CrossRefGoogle Scholar
  91. Stossi F, Likhite VS, Katzenellenbogen JA, Katzenellenbogen BS (2006) Estrogen-occupied estrogen receptor represses cyclin G2 gene expression and recruits a repressor complex at the cyclin G2 promoter. J Biol Chem 281:16272–16278.PubMedCrossRefGoogle Scholar
  92. Suzuki T, Shoji S, Yamamoto K, Nada S, Okada M, Yamamoto T, Honda Z (1998) Essential roles of lyn in fibronectin-mediated filamentous actin assembly and cell motility in mast cells. J Immunol 161:3694–3701.PubMedGoogle Scholar
  93. Townsend PA, Stephanou A, Packham G, Latchman DS (2005) Bag-1: a multi-functional pro-survival molecule. Int J Biochem Cell Biol 37:251–259.PubMedCrossRefGoogle Scholar
  94. Treeck O, Zhou R, Diedrich K, Ortmann O (2004) Tamoxifen long-term treatment in vitro alters the apoptotic response of MCF-7 breast cancer cells. Anticancer Drugs 15:787–793.PubMedCrossRefGoogle Scholar
  95. Tsai MS, Shamon-Taylor LA, Mehmi I, Tang CK, Lupu R (2003) Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer. Oncogene 22:761–768.PubMedCrossRefGoogle Scholar
  96. Valentine JE, Kalkhoven E, White R, Hoare S, Parker MG (2000) Mutations in the estrogen receptor ligand binding domain discriminate between hormone-dependent transactivation and transrepression. J Biol Chem 275:25322–25329.PubMedCrossRefGoogle Scholar
  97. Van Agthoven T, van Agthoven TL, Dekker A, Foekens JA, Dorssers LC (1994) Induction of estrogen independence of ZR-75-1 human breast cancer cells by epigenetic alterations. Mol Endocrinol 8:1474–1483.PubMedCrossRefGoogle Scholar
  98. Vieth M, Sutherland JJ, Robertson DH, Campbell RM (2005) Kinomics: characterizing the therapeutically validated kinase space. Drug Discov Today 10:839–846.PubMedCrossRefGoogle Scholar
  99. Widschwendter M, Jones PA (2002) DNA methylation and breast carcinogenesis. Oncogene 21:5462–5482.PubMedCrossRefGoogle Scholar
  100. Wilson MA, Chrysogelos SA (2002) Identification and characterization of a negative regulatory element within the epidermal growth factor receptor gene first intron in hormone-dependent breast cancer cells. J Cell Biochem 85:601–614.PubMedCrossRefGoogle Scholar
  101. Wu JT, Kral JG (2005) The NF-kappaB/IkappaB signaling system: a molecular target in breast cancer therapy. J Surg Res 123:158–169.PubMedCrossRefGoogle Scholar
  102. Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG, Darnay BG, Lamothe B, Sun H, Talpaz M, Donato NJ (2008) Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst 100:926–939.PubMedCrossRefGoogle Scholar
  103. Wu M, Soler DR, Abba MC, Nunez MI, Baer R, Hatzis C, Llombart-Cussac A, Llombart-Bosch A, Aldaz CM (2007) CtIP silencing as a novel mechanism of tamoxifen resistance in breast cancer. Mol Cancer Res 5:1285–1295.PubMedCrossRefGoogle Scholar
  104. Yarden RI, Wilson MA, Chrysogelos SA (2001) Estrogen suppression of EGFR expression in breast cancer cells: a possible mechanism to modulate growth. J Cell Biochem 81:232–246.CrossRefGoogle Scholar
  105. Ye Y, Xiao Y, Wang W, Yearsley K, Gao JX, Barsky SH (2008) ERalpha suppresses slug expression directly by transcriptional repression. Biochem J 416(2):179–8.CrossRefGoogle Scholar
  106. Zhou Y, Eppenberger-Castori S, Eppenberger U, Benz CC (2005) The NFkappaB pathway and endocrine-resistant breast cancer. Endocr Relat Cancer 12:S37–S46.PubMedCrossRefGoogle Scholar
  107. Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, Eppenberger U, Eppenberger-Castori S, Benz CC (2007) Enhanced NF kappa b and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer 7:59.PubMedCrossRefGoogle Scholar
  108. Zubairy S, Oesterreich S (2005) Estrogen-repressed genes- key mediators of estrogen action? Breast Cancer Res 7:163–16.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Julia M.W. Gee
    • 1
  • Andrew Stone
  • Richard A. McClelland
  • Stephen Hiscox
  • Iain R. Hutcheson
  • Nicola J. Jordan
  • Heidi M. Fiegl
  • Martin Widschwendter
  • Victoria E. Shaw
  • Denise Barrow
  • Robert I. Nicholson
  1. 1.Tenovus Centre for Cancer Research Welsh School of PharmacyCardiff UniversityUK

Personalised recommendations