The Re-Expression of Estrogen Receptor in Estrogen Receptor-Negative Breast Cancer and Restoration of Anti-Estrogen Responses

  • Jill Bayliss
  • Amy Hilger
  • Prakash Vishnu
  • Kathleen Diehl
  • Dorraya El-Ashry


Loss of estrogen receptor α ERα in breast cancer correlates with a more aggressive, tamoxifen resistant phenotype. ERα-negative tumors often display overexpression or amplification of growth factor receptors of the erbB family, particularly EGFR and erbB-2, and consequently, elevated growth factor signaling and resultant MAP kinase (ERK) activity. We have previously shown that overexpression/hyperactivation of EGFR or erbB-2, or the downstream effectors Raf or MEK, in ERα+, estrogen-dependent MCF-7 cells results in the acquisition of estrogen-independence and loss of ERα expression. We have shown that the common downstream effector of ERα downregulation in all our model cell lines is hyperactive MAPK and that inhibition of this hyperactive MAPK restores ERα expression. Microarray expression profiling of these hyperactive MAPK model cell lines revealed a hyperactive MAPK signature that correlates with ERα-breast cancer and not ERα+ breast cancer. We have more recently extended these observations to established ERα-breast cancer cell lines and primary cultures from ERα-breast tumor specimens. Inhibition of MAPK in these ERα-breast cancer cells restores ERα expression and associated with this re-expression of ERα is the acquisition of anti-estrogen responses. These data demonstrate the dynamic nature of ERα expression in breast cancer cells and the ability to impact ERα expression by altering cellular signaling pathways. Further, they suggest a potential novel therapeutic strategy for ERα-breast cancer: inhibition of MAPK activity to restore both ERα expression and anti-estrogen responses.


Estrogen receptor loss MAPK Microarray profiling 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allred DC, Mohsin SK, Fuqua SA (2001) Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer 8:47–61.PubMedCrossRefGoogle Scholar
  2. Anderson E, Clarke RB, Howell A (1998) Estrogen responsiveness and control of normal human breast proliferation [see comments]. J Mammary Gland Biol Neoplasia 3:23–35.PubMedCrossRefGoogle Scholar
  3. Ballare C, Bravo AI, Laucella S, Sorin I, Cerdeiro R, Loza J, Sousa MF, Guman N, Mordoh J (1989) DNA synthesis in estrogen receptor-positive human breast cancer takes place preferentially in estrogen receptor-negative cells. Cancer 64:842–848.PubMedCrossRefGoogle Scholar
  4. Bayliss J, Hilger A, Vishnu P, Diehl K, El-Ashry D (2007) Reversal of the estrogen receptor-negative phenotype and restoration of anti-estrogen response in breast cancer. Clin Canc Res 13:7029–7039.CrossRefGoogle Scholar
  5. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276:9817–982.PubMedCrossRefGoogle Scholar
  6. Cheng G, Weihua Z, Warner M, Gustafsson JA (2004) Estrogen receptors ER alpha and ER beta in proliferation in the rodent mammary gland. Proc Natl Acad Sci U S A 101:3739–3746.PubMedCrossRefGoogle Scholar
  7. 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
  8. Clark GM, McGuire WL (1988) Steroid receptors and other prognostic factors in primary breast cancer. Semin Oncol 15:20–25.PubMedGoogle Scholar
  9. Clarke RB, Howell A, Potten CS, Anderson E (1997) Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 57:4987–4991.PubMedGoogle Scholar
  10. Creighton C, Hilger A, Murthy S, Rae J, Chinnaiyan A, El-Ashry D (2006) Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res 66:3903–3911.PubMedCrossRefGoogle Scholar
  11. Daniel CW, Silberstein GB, Strickland P (1987) Direct action of 17 beta-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. Cancer Res 47:6052–6057.PubMedGoogle Scholar
  12. De Sombre ER, Thorpe SM, Rose C, Blough RR, Andersen KW, Rasmussen BB, King WJ (1986) Prognostic usefulness of estrogen receptor immunocytochemical assays for human breast cancer. Cancer Res 46:4256s–4264s.Google Scholar
  13. Degraffenried LA, Chandrasekar B, Friedrichs WE, Donzis E, Silva J, Hidalgo M, Freeman JW, Weiss GR (2004) NF-kappa B inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen. Ann Oncol 15:885–890.PubMedCrossRefGoogle Scholar
  14. DiGiovanna MP, Chu P, Davison TL, Howe CL, Carter D, Claus EB, Stern DF (2002) Active signaling by HER-2/neu in a subpopulation of HER-2/neu-overexpressing ductal carcinoma in situ: clinicopathological correlates. Cancer Res 62:6667–6673.PubMedGoogle Scholar
  15. Early Breast Cancer Trialists Collaborative Group Tamoxifen for early breast cancer: an overview of the randomized trials. 1998. p. 1451 (Abstract)Google Scholar
  16. El-Ashry D, Miller DL, Kharbanda S, Lippman ME, Kern FG (1996) Constitutive raf-1 kinase activity in breast cancer cells induces both estrogen-independent growth and apoptosis. Oncogene 15:423–435.CrossRefGoogle Scholar
  17. Fanelli MA, Vargas-Roig LM, Gago FE, Tello O, Lucero DA, Ciocca DR (1996) Estrogen receptors, progesterone receptors, and cell proliferation in human breast cancer. Breast Cancer Res Treat 37:217–228.PubMedCrossRefGoogle Scholar
  18. Fantl WJ, Johnson DE, Williams LT (1993) Signalling by receptor tyrosine kinases. Annu Rev Biochem 62:453–481.PubMedGoogle Scholar
  19. Ferguson AT, Lapidus RG, Baylin SB, Davidson NE (1995) Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res 55:2279–2283.PubMedGoogle Scholar
  20. Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg AA, Ferno M, Peterson C, Meltzer PS (2001) Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res 61:5979–5984.PubMedGoogle Scholar
  21. Gusterson BA (1992) Identification and interpretation of epidermal growth factor and c-erbB-2 overexpression. Eur J Cancer 28:263–267.PubMedCrossRefGoogle Scholar
  22. Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481.PubMedGoogle Scholar
  23. 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-kappaB. Mol Endocrinol 18:1396–1410.PubMedCrossRefGoogle Scholar
  24. Huang E, Cheng SH, Dressman H, Pittman J, Tsou MH, Horng CF, Bild A, Iversen ES, Liao M, Chen CM, West M, Nevins JR, Huang AT (2003) Gene expression predictors of breast cancer outcomes. Lancet 361:1590–1596.PubMedCrossRefGoogle Scholar
  25. Jacquemier JD, Hassoun J, Torrente M, Martin PM (1990) Distribution of estrogen and progesterone receptors in healthy tissue adjacent to breast lesions at various stages–immunohistochemical study of 107 cases. Breast Cancer Res Treat 15:109–117.PubMedCrossRefGoogle Scholar
  26. Jakesz R, Smith CA, Aitken S, Huff K, Schuette W, Shackney S, Lippman M (1984) Influence of cell proliferation and cell cycle phase on expression of estrogen receptor in MCF-7 breast cancer cells. Cancer Res 44:619–625.PubMedGoogle Scholar
  27. Johnston SR (1997) Acquired tamoxifen resistance in human breast cancer–potential mechanisms and clinical implications. Anticancer Drugs 8:911-930.PubMedCrossRefGoogle Scholar
  28. Johnston SR, Saccani-Jotti G, Smith IE, Salter J, Newby J, Coppen M, Ebbs SR, Dowsett M (1995) Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res 55:3331–3338.PubMedGoogle Scholar
  29. Keen JC, Yan L, Mack KM, Pettit C, Smith D, Sharma D, Davidson NE (2003) A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor alpha (ER) in ER negative human breast cancer cells in combination with 5-aza 2’-deoxycytidine. Breast Cancer Res Treat 81:177–186.PubMedCrossRefGoogle Scholar
  30. Knight WA, Livingston RB, Gregory EJ, McGuire WL (1977) Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer. Cancer Res 37:4669–4671.PubMedGoogle Scholar
  31. Kobayashi S, Iwase H, Itoh Y, Fukuoka H, Yamashita H, Kuzushima T, Iwata H, Masaoka A, Kimura N (1992) Estrogen receptor, c-erbB-2 and nm23/NDP kinase expression in the intraductal and invasive components of human breast cancers. Jpn J Cancer Res 83:859–865.PubMedGoogle Scholar
  32. Koerner F, Oyama T, Kurosumi M, Maluf (2001) Ovarian hormone receptors in human mammary stromal cells. J Steroid Biochem Mol Biol 78:285–290.Google Scholar
  33. Kurebayashi J, Otsuki T, Kunisue H, Tanaka K, Yamamoto S, Sonoo H (2000) Expression levels of estrogen receptor-alpha, estrogen receptor-beta, coactivators, and corepressors in breast cancer. Clin Cancer Res 6:512–518.PubMedGoogle Scholar
  34. Lapidus RG, Ferguson AT, Ottaviano YL, Parl FF, Smith HS, Weitzman SA, Baylin SB, Issa J PJ, Davidson NE (1996) Methylation of estrogen and progesterone receptor genes $5$ CpG islands correlates with ER and PR gene expression in breast tumors. Clin Cancer Res 2:805–810.PubMedGoogle Scholar
  35. Lapidus RG, Nass SJ, Butash KA, Parl FF, Weitzman SA, Graff JG, Herman JG, Davidson NE (1998) Mapping of ER gene CpG island methylation-specific polymerase chain reaction. Cancer Res 58:2515–2519.PubMedGoogle Scholar
  36. Liu Y, El-Ashry D, Chen D, Ding IYF, Kern FG (1995) MCF-7 breast cancer cells overexpressing transfected c-erb B-2 have an in vitro growth advantage in estrogen-depleted conditions and reduced estrogen-dependence and tamoxifen-sensitivity in vivo. Breast Cancer Res Treat 34:97–117.PubMedCrossRefGoogle Scholar
  37. Massarweh S, Osborne CK, Jiang S, Wakeling AE, Rimawi M, Mohsin SK, Hilsenbeck S, Schiff R (2006) Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer. Cancer Res 66:8266–8273.PubMedCrossRefGoogle Scholar
  38. McGuire WL, Tandon AK, Allred DC, Chamness GC, Clark GM (1990) How to use prognostic factors in axillary node-negative breast cancer patients [see comments]. J Natl Cancer Inst 82:1006–1015.PubMedCrossRefGoogle Scholar
  39. Miller DL, El-Ashry D, Cheville AL, Liu Y, McLeskey SW, Kern FG (1994) Emergence of MCF-7 cells overexpressing a transfected epidermal growth factor receptor (EGFR) under estrogen-depleted conditions: evidence for a role of EGFR in breast cancer growth and progression. Cell Growth Differ 5:1263–1274.PubMedGoogle Scholar
  40. Munzone E, Curigliano G, Rocca A, Bonizzi G, Renne G, Goldhirsch A, Nole 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
  41. Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ Jr, Sledge GW Jr (1997) Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17:3629–3639.PubMedGoogle Scholar
  42. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, Speed T, Spellman PT, DeVries S, Lapuk A, Wang NJ, Kuo WL, Sitlwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gasdar A, Gray JW (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10:515–527.Google Scholar
  43. Newby JC, Johnston SR, Smith IE, Dowsett M (1997) Expression of epidermal growth factor receptor and c-erB2 during the development of tamoxifen resistance in human breast cancer. Clin Cancer Res 3:1643–1651.Google Scholar
  44. Nicholson S, Halcrow P, Sainsbury JR, Angus B, Chambers P, Farndon JR, Harris AL (1988) Epidermal growth factor receptor (EGFR) status associated with failure of primary endocrine therapy in elderly postmenopausal patients with breast cancer. Br J Cancer 58:810–814.PubMedGoogle Scholar
  45. Nicholson S, Richard J, Sainsbury C, Halcrow P, Kelly P, Angus B, Wright C, Henry J, Farndon JR, Harris AL (1991) Epidermal growth factor receptor (EGFR); results of a 6 year follow-up study in operable breast cancer with emphasis on the node negative subgroup. Br J Cancer 63:146–150.PubMedGoogle Scholar
  46. Nicholson S, Sainsbury JR, Halcrow P, Chambers P, Farndon JR, Harris AL (1989) Expression of epidermal growth factor receptors associated with lack of response to endocrine therapy in recurrent breast cancer. Lancet 1:182–185.PubMedCrossRefGoogle Scholar
  47. Oh AS, Lorant LA, Holloway JN, Miller DL, Kern FG, El-Ashry D (2001) Hyperactivation of MAPK induces loss of eralpha expression in breast cancer cells. Mol Endocrinol 15:1344–1359.PubMedCrossRefGoogle Scholar
  48. Ottaviano YL, Issa JP, Parl FF, Smith HS, Baylin SB, Davidson NE (1994) Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res 54:2552–2555.PubMedGoogle Scholar
  49. Pan Q, Kleer CG, van Golen KL, Irani J, Bottema KM, Bias C, DeCarvalho M, Mesri EA, Robins DM, Dick RD, Brewer GJ, Merajver SD (2002) Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res 62:4854–4859.PubMedGoogle Scholar
  50. Panahy C, Puddefoot JR, Anderson E, Vinson GP, Berry CL, Turner MJ, Brown CL, Goode AW (1987) Oestrogen and progesterone receptor distribution in the cancerous breast. Br J Cancer 55:459–462.PubMedGoogle Scholar
  51. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752.PubMedCrossRefGoogle Scholar
  52. Perren TJ (1991) Cv-erbB-2 oncogene as a prognostic marker in breast cancer [editorial]. Br J Cancer 63:328–332.PubMedGoogle Scholar
  53. Petersen OW, Hoyer PE, Van Deurs B (1987) Frequency and distribution of estrogen receptor-positive cells in normal, nonlactating human breast tissue. Cancer Res 47:5748–5751.PubMedGoogle Scholar
  54. Pujol P, Hilsenbeck SG, Chamness GC, Elledge RM (1994) Rising levels of estrogen receptor in breast cancer over 2 decades [see comments]. Cancer 74:1601–1606.Google Scholar
  55. 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
  56. Roger P, Daures JP, Maudelonde T, Pignodel C, Gleizes M, Chapelle J, Marty-Double C, Baldet P, Mares P, Laffargue F, Rochefort H (2000) Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors. Hum Pathol 31:593–600.PubMedCrossRefGoogle Scholar
  57. Rostagno P, Moll JL, Birtwisle-Peyrottes I, Ettore F, Caldani C (1996) Cell cycle expression of estrogen receptors determined by image analysis on human breast cancer cells in vitro and in vivo. Breast Cancer Res Treat 39:147–154.PubMedCrossRefGoogle Scholar
  58. Russo J, Ao X, Grill C, Russo IH (1999) Pattern of distribution of cells positive for estrogen receptor alpha and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res Treat 53:217–227.PubMedCrossRefGoogle Scholar
  59. Sainsbury JR, Farndon JR, Needham GK, Malcolm AJ, Harris AL (1987) Epidermal-growth-factor receptor status as predictor of early recurrence of and death from breast cancer. Lancet 1:1398–1402.PubMedGoogle Scholar
  60. Sainsbury JR, Farndon JR, Sherbet GV, Harris AL (1985) Epidermal-growth-factor receptors and oestrogen receptors in human breast cancer. Lancet 1:364–366.PubMedCrossRefGoogle Scholar
  61. Sharma AK, Horgan K, Douglas-Jones A, McClelland R, Gee J, Nicholson R (1994a) Dual immunocytochemical analysis of oestrogenand epidermal growth factor receptors in human breast cancer. Br J Cancer 69:1032–1037.Google Scholar
  62. Sharma AK, Horgan K, McClelland RA, Douglas-Jones AG, Van Agthoven T, Dorssers LC, Nicholson RI (1994b) A dual immunocytochemical assay for oestrogen and epidermal growth factor receptors in tumour cell lines. Histochem J 26:306–310.CrossRefGoogle Scholar
  63. Shoker BS, Jarvis C, Clarke RB, Anderson E, Hewlett J, Davies MP, Sibson DR, Sloane JP (1999a) Estrogen receptor-positive proliferating cells in the normal and precancerous breast. Am J Pathol 155:1811–1815.Google Scholar
  64. Shoker BS, Jarvis C, Sibson DR, Walker C, Sloane JP (1999b) Oestrogen receptor expression in the normal and pre-cancerous breast [see comments]. J Pathol 188:237–244.Google Scholar
  65. Silvistrini R, Daidone MG, Di Fronzo G (1979) Relationship between proliferative activity and estrogen receptors in breast cancer. Cancer 44:665–670.CrossRefGoogle Scholar
  66. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182.PubMedCrossRefGoogle Scholar
  67. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869–10874.PubMedCrossRefGoogle Scholar
  68. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsoen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418–8423.PubMedCrossRefGoogle Scholar
  69. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 100:10393–10398.Google Scholar
  70. Terenius L, Johansson H, Rimsten A, Thoren L (1974) Malignant and benign human mammary disease: estrogen binding in relation to clinical data. Cancer 33:1364–1368.PubMedCrossRefGoogle Scholar
  71. Toi M, Osaki A, Yamada H, Toge T (1991) Epidermal growth factor receptor expression as a prognostic indicator in breast cancer. Eur J Cancer 27:977–980.PubMedCrossRefGoogle Scholar
  72. Toi M, Tominaga T, Osaki A, Toge T (1994) Role of epidermal growth factor receptor expression in primary breast cancer: results of a biochemical study and an immunocytochemical study. Breast Cancer Res Treat 29:51–58.PubMedCrossRefGoogle Scholar
  73. Toi M, Wada T, Yamada H, Ohsaki A, Yamamoto A, Nakamura T, Niimoto M, Hattori T (1990) Growth fractions of breast cancer in relation to epidermal growth factor receptor and estrogen receptor. Jpn J Surg 20:327–330.PubMedCrossRefGoogle Scholar
  74. Van Agthoven T, Timmermans M, Foekens JA, Dorssers LC, Henzen-Logmans SC (1994) Differential expression of estrogen, progesterone, and epidermal growth factor receptors in normal, benign, and malignant human breast tissues using dual staining immunohistochemistry. Am J Pathol 144:1238–1246.PubMedGoogle Scholar
  75. van Golen KL, Wu ZF, Qiao XT, Bao L, Merajver SD (2000a) RhoC GTPase overexpression modulates induction of angiogenic factors in breast cells. Neoplasia 2:418–425.CrossRefGoogle Scholar
  76. van Golen KL, Wu ZF, Qiao XT, Bao LW, Merajver SD (2000b) RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res 60:5832–5838.Google Scholar
  77. Van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der KK, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536.CrossRefGoogle Scholar
  78. Vollmer G, Gerdes J, Knuppen R (1989) Relationship of cytosolic estrogen and progesterone receptor content and the growth fraction in human mammary carcinomas. Cancer Res 49: 4011–4014.PubMedGoogle Scholar
  79. Walker KJ, McClelland RA, Candlish W, Blamey RW, Nicholson RI (1992) Heterogeneity of oestrogen receptor expression in normal and malignant breast tissue. Eur J Cancer 28: 34–37.PubMedCrossRefGoogle Scholar
  80. Wittliff JL, Hilf R, Brooks WF Jr, Savlov ED, Hall TC, Orlando RA (1972) Specific estrogen-binding capacity of the cytoplasmic receptor in normal and neoplastic breast tissues of humans. Cancer Res 32:1983–1992.PubMedGoogle Scholar
  81. Yang X, Ferguson AT, Nass SJ, Phillips DL, Butash KA, Wang SM, Herman JG, Davidson NE (2000) Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition. Cancer Res 60:6890–6894.PubMedGoogle Scholar
  82. Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG, Davidson NE (2001) Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. Cancer Res 61:7025–7029.Google Scholar
  83. Zhou Q, Atadja P, Davidson NE (2007) Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol. Ther 6:64–69.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Jill Bayliss
  • Amy Hilger
  • Prakash Vishnu
  • Kathleen Diehl
  • Dorraya El-Ashry
    • 1
  1. 1.Department of Internal Medicine Division of Hematology/OncologyUniversity of Miami Miller School of MedicineMiamiUSA

Personalised recommendations