Advertisement

Use of Epigenetic Modulators as a Powerful Adjuvant for Breast Cancer Therapies

  • Aurore Claude-Taupin
  • Michael Boyer-Guittaut
  • Régis Delage-Mourroux
  • Eric HervouetEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1238)

Abstract

Breast cancer (BC) is one of the five most frequent cancers in the world. Despite earlier diagnosis and development of specific treatments, mortality has only declined of about 30 % during the past two decades. Two of the main reasons are the emergence of drug resistance and the absence of specific therapy for triple negative breast cancers (TNBC), which are characterized by a poor prognosis due to high proliferation rate. Therefore, the future goal of the fight against BC will be to find new therapeutic approaches to overcome drug resistances and cure TNBC. Recent research on gene expression profiles linked to the different types of BC cells have led to consider the use of epigenetic modulators to modulate the expression of genes deregulated in cancer. The preliminary encouraging results have demonstrated a positive effect of DNA Methyl Transferase (DNMT) and Histone DeAcetylase (HDAC) inhibitors on different types of BC, as well as drug-resistant cells, with low side effects. In this review, we will describe the different epigenetic modulators currently used or investigated in BC therapy research in vitro as well as preclinical and clinical trials, and promising compounds, which might be used in future BC therapies.

Key words

Breast cancer DNA DNMT DNMTi Epigenetic HDAC HDACi Histone Methylation Therapy 

Abbreviations

ATF

Artificial transcription factor

BC

Breast cancer

DCIS

Ductal carcinoma in situ

DNMT

DNA methyl transferase

ER

Estrogen receptor

HDAC

Histone deacetylase

HER2

Human epidermal growth factor receptor 2

PR

Progesterone receptor

SAHA

Suberoylanilide hydroxamic acid

TNBC

Triple negative breast cancer

TSA

Trichostatin A

TSG

Tumor suppressor gene

VPA

Valproic acid

References

  1. 1.
    Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917. doi: 10.1002/ijc.25516 PubMedCrossRefGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30. doi: 10.3322/caac.21166 PubMedCrossRefGoogle Scholar
  3. 3.
    Antoniou AC, Easton DF (2006) Models of genetic susceptibility to breast cancer. Oncogene 25:5898–5905. doi: 10.1038/sj.onc.1209879 PubMedCrossRefGoogle Scholar
  4. 4.
    Rivenbark AG, O’Connor SM, Coleman WB (2013) Molecular and cellular heterogeneity in breast cancer: challenges for personalized medicine. Am J Pathol 183:1113–1124. doi: 10.1016/j.ajpath.2013.08.002.Google Scholar
  5. 5.
    Narod S, Lynch H, Conway T, Watson P, Feunteun J, Lenoir G (1993) Increasing incidence of breast cancer in family with BRCA1 mutation. Lancet 341:1101–1102PubMedCrossRefGoogle Scholar
  6. 6.
    Dammann R, Schagdarsurengin U, Strunnikova M, Rastetter M, Seidel C, Liu L, Tommasi S, Pfeifer GP (2003) Epigenetic inactivation of the Ras-association domain family 1 (RASSF1A) gene and its function in human carcinogenesis. Histol Histopathol 18:665–677PubMedGoogle Scholar
  7. 7.
    Gupta A, Godwin AK, Vanderveer L, Lu A, Liu J (2003) Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res 63:664–673PubMedGoogle Scholar
  8. 8.
    Mohamed A, Krajewski K, Cakar B, Ma CX (2013) Targeted therapy for breast cancer Am J Pathol 183:1096–1112. doi: 10.1016/j.ajpath.2013.07.005Google Scholar
  9. 9.
    Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12:R68. doi: 10.1186/bcr2635 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES (2011) Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 18:333–345. doi: 10.1530/ERC-10-0262 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Foekens JA, Peters HA, Grebenchtchikov N, Look MP, Meijer-van Gelder ME, Geurts-Moespot A, van der Kwast TH, Sweep CG, Klijn JG (2001) High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 61:5407–5414PubMedGoogle Scholar
  12. 12.
    Pathiraja TN, Stearns V, Oesterreich S (2010) Epigenetic regulation in estrogen receptor positive breast cancer—role in treatment response. J Mammary Gland Biol Neoplasia 15:35–47. doi: 10.1007/s10911-010-9166-0 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Sharma D, Saxena NK, Davidson NE, Vertino PM (2006) Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: tamoxifen-bound reactivated ER recruits distinctive corepressor complexes. Cancer Res 66:6370–6378. doi: 10.1158/0008-5472.CAN-06-0402 PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Szyf M (2009) Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol 49:243–263. doi: 10.1146/annurev-pharmtox-061008-103102 PubMedCrossRefGoogle Scholar
  15. 15.
    Hurtubise A, Momparler RL (2006) Effect of histone deacetylase inhibitor LAQ824 on antineoplastic action of 5-Aza-2’-deoxycytidine (decitabine) on human breast carcinoma cells. Cancer Chemother Pharmacol 58:618–625. doi: 10.1007/s00280-006-0225-6 PubMedCrossRefGoogle Scholar
  16. 16.
    Bovenzi V, Momparler RL (2001) Antineoplastic action of 5-aza-2’-deoxycytidine and histone deacetylase inhibitor and their effect on the expression of retinoic acid receptor beta and estrogen receptor alpha genes in breast carcinoma cells. Cancer Chemother Pharmacol 48:71–76PubMedCrossRefGoogle Scholar
  17. 17.
    Qu Z, Fu J, Yan P, Hu J, Cheng S-Y, Xiao G (2010) Epigenetic repression of PDZ-LIM domain-containing protein 2 implications for the biology and treatment of breast cancer. J Biol Chem 285:11786–11792. doi: 10.1074/jbc.M109.086561 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Das PM, Thor AD, Edgerton SM, Barry SK, Chen DF, Jones FE (2010) Reactivation of epigenetically silenced HER4/ERBB4 results in apoptosis of breast tumor cells. Oncogene 29:5214–5219. doi: 10.1038/onc.2010.271 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Yin X, Xiang T, Li L, Su X, Shu X, Luo X, Huang J, Yuan Y, Peng W, Oberst M, Kelly K, Ren G, Tao Q (2013) DACT1, an antagonist to Wnt/β-catenin signaling, suppresses tumor cell growth and is frequently silenced in breast cancer. Breast Cancer Res 15:R23. doi: 10.1186/bcr3399 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Borges S, Döppler H, Perez EA, Andorfer CA, Sun Z, Anastasiadis PZ, Thompson EA, Geiger XJ, Storz P (2013) Pharmacologic reversion of epigenetic silencing of the PRKD1 promoter blocks breast tumor cell invasion and metastasis. Breast Cancer Res 15:R66. doi: 10.1186/bcr3460 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Ateeq B, Unterberger A, Szyf M, Rabbani SA (2008) Pharmacological inhibition of DNA methylation induces proinvasive and prometastatic genes in vitro and in vivo. Neoplasia 10:266–278PubMedCentralPubMedGoogle Scholar
  22. 22.
    Singh KP, Treas J, Tyagi T, Gao W (2012) DNA demethylation by 5-aza-2-deoxycytidine treatment abrogates 17 beta-estradiol-induced cell growth and restores expression of DNA repair genes in human breast cancer cells. Cancer Lett 316:62–69. doi: 10.1016/j.canlet.2011.10.022 PubMedCrossRefGoogle Scholar
  23. 23.
    Di Cello F, Cope L, Li H, Jeschke J, Wang W, Baylin SB, Zahnow CA (2013) Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer. PLoS ONE 8:e68630. doi: 10.1371/journal.pone.0068630 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Zeng L, Jarrett C, Brown K, Gillespie KM, Holly JMP, Perks CM (2013) Insulin-like growth factor binding protein-3 (IGFBP-3) plays a role in the anti-tumorigenic effects of 5-Aza-2′-deoxycytidine (AZA) in breast cancer cells. Exp Cell Res 319:2282–2295. doi: 10.1016/j.yexcr.2013.06.011 PubMedCrossRefGoogle Scholar
  25. 25.
    Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG, Davidson NE (2001) Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells. Cancer Res 61:7025–7029PubMedGoogle Scholar
  26. 26.
    Ari F, Napieralski R, Ulukaya E, Dere E, Colling C, Honert K, Krüger A, Kiechle M, Schmitt M (2011) Modulation of protein expression levels and DNA methylation status of breast cancer metastasis genes by anthracycline-based chemotherapy and the demethylating agent decitabine. Cell Biochem Funct 29:651–659. doi: 10.1002/cbf.1801 PubMedCrossRefGoogle Scholar
  27. 27.
    Pryzbylkowski P, Obajimi O, Keen JC (2008) Trichostatin A and 5 Aza-2′ deoxycytidine decrease estrogen receptor mRNA stability in ER positive MCF7 cells through modulation of HuR. Breast Cancer Res Treat 111:15–25. doi: 10.1007/s10549-007-9751-0 PubMedCrossRefGoogle Scholar
  28. 28.
    Jawaid K, Crane SR, Nowers JL, Lacey M, Whitehead SA (2010) Long-term genistein treatment of MCF-7 cells decreases acetylated histone 3 expression and alters growth responses to mitogens and histone deacetylase inhibitors. J Steroid Biochem Mol Biol 120:164–171. doi: 10.1016/j.jsbmb.2010.04.007 PubMedCrossRefGoogle Scholar
  29. 29.
    Sandhu R, Rivenbark AG, Coleman WB (2012) Enhancement of chemotherapeutic efficacy in hypermethylator breast cancer cells through targeted and pharmacologic inhibition of DNMT3b. Breast Cancer Res Treat 131:385–399. doi: 10.1007/s10549-011-1409-2 PubMedCrossRefGoogle Scholar
  30. 30.
    Mirza S, Sharma G, Pandya P, Ralhan R (2010) Demethylating agent 5-aza-2-deoxycytidine enhances susceptibility of breast cancer cells to anticancer agents. Mol Cell Biochem 342:101–109. doi: 10.1007/s11010-010-0473-y PubMedCrossRefGoogle Scholar
  31. 31.
    Vijayaraghavalu S, Peetla C, Lu S, Labhasetwar V (2012) Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions. Mol Pharm 9:2730–2742. doi: 10.1021/mp300281t PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Vijayaraghavalu S, Dermawan JK, Cheriyath V, Labhasetwar V (2013) Highly synergistic effect of sequential treatment with epigenetic and anticancer drugs to overcome drug resistance in breast cancer cells is mediated via activation of p21 gene expression leading to G2/M cycle arrest. Mol Pharm 10:337–352. doi: 10.1021/mp3004622 PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Bianco C, Castro NP, Baraty C, Rollman K, Held N, Rangel MC, Karasawa H, Gonzales M, Strizzi L, Salomon DS (2013) Regulation of human Cripto-1 expression by nuclear receptors and DNA promoter methylation in human embryonal and breast cancer cells. J Cell Physiol 228:1174–1188. doi: 10.1002/jcp.24271 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Stone A, Valdés-Mora F, Gee JMW, Farrow L, McClelland RA, Fiegl H, Dutkowski C, McCloy RA, Sutherland RL, Musgrove EA, Nicholson RI (2012) Tamoxifen-induced epigenetic silencing of oestrogen-regulated genes in anti-hormone resistant breast cancer. PLoS ONE 7:e40466. doi: 10.1371/journal.pone.0040466 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Thakur S, Feng X, Qiao Shi Z, Ganapathy A, Kumar Mishra M, Atadja P, Morris D, Riabowol K (2012) ING1 and 5-azacytidine act synergistically to block breast cancer cell growth. PLoS One 7:e43671. doi: 10.1371/journal.pone.0043671 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Tikoo K, Ali IY, Gupta J, Gupta C (2009) 5-Azacytidine prevents cisplatin induced nephrotoxicity and potentiates anticancer activity of cisplatin by involving inhibition of metallothionein, pAKT and DNMT1 expression in chemical induced cancer rats. Toxicol Lett 191:158–166. doi: 10.1016/j.toxlet.2009.08.018 PubMedCrossRefGoogle Scholar
  37. 37.
    Weber J (2002) NCT00030615. Decitabine in treating patients with advanced solid tumors. https://clinicaltrials.gov
  38. 38.
    Aparicio A, Eads CA, Leong LA, Laird PW, Newman EM, Synold TW, Baker SD, Zhao M, Weber JS (2003) Phase I trial of continuous infusion 5-aza-2’-deoxycytidine. Cancer Chemother Pharmacol 51:231–239. doi: 10.1007/s00280-002-0563-y PubMedGoogle Scholar
  39. 39.
    Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schätzlein A, Twelves C, Kaye SB, Brown R (2007) Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol Off J Am Soc Clin Oncol 25:4603–4609. doi: 10.1200/JCO.2007.10.8688 CrossRefGoogle Scholar
  40. 40.
    Khong HT (2008) NCT00748553. A phase I/II clinical trial of vidaza with abraxane in the treatment of patients with advanced or metastatic solid tumors and breast cancer (VA). https://clinicaltrials.gov
  41. 41.
    Feng W, Lu Z, Luo RZ, Zhang X, Seto E, Liao WS-L, Yu Y (2007) Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer. Int J Cancer 120:1664–1668. doi: 10.1002/ijc.22474 PubMedCrossRefGoogle Scholar
  42. 42.
    Yarosh W, Barrientos T, Esmailpour T, Lin L, Carpenter PM, Osann K, Anton-Culver H, Huang T (2008) TBX3 is overexpressed in breast cancer and represses p14 ARF by interacting with histone deacetylases. Cancer Res 68:693–699. doi: 10.1158/0008-5472.CAN-07-5012 PubMedCrossRefGoogle Scholar
  43. 43.
    Chakravarty G, Rider B, Mondal D (2011) Cytoplasmic compartmentalization of SOX9 abrogates the growth arrest response of breast cancer cells that can be rescued by trichostatin A treatment. Cancer Biol Ther 11:71–83. doi: 10.4161/cbt.11.1.13952 PubMedCrossRefGoogle Scholar
  44. 44.
    Kim S-H, Kang H-J, Na H, Lee M-O (2010) Trichostatin A enhances acetylation as well as protein stability of ERalpha through induction of p300 protein. Breast Cancer Res 12:R22. doi: 10.1186/bcr2562 PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Reid G, Métivier R, Lin C-Y, Denger S, Ibberson D, Ivacevic T, Brand H, Benes V, Liu ET, Gannon F (2005) Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor alpha, in response to deacetylase inhibition by valproic acid and trichostatin A. Oncogene 24:4894–4907. doi: 10.1038/sj.onc.1208662 PubMedCrossRefGoogle Scholar
  46. 46.
    Jang ER, Lim S-J, Lee ES, Jeong G, Kim T-Y, Bang Y-J, Lee J-S (2003) The histone deacetylase inhibitor trichostatin A sensitizes estrogen receptor α-negative breast cancer cells to tamoxifen. Oncogene 23:1724–1736. doi: 10.1038/sj.onc.1207315 CrossRefGoogle Scholar
  47. 47.
    Collins-Burow B (2011) The histone deacetylase inhibitor trichostatin A alters microRNA expression profiles in apoptosis-resistant breast cancer cells. Oncol Rep. doi: 10.3892/or.2011.1488 PubMedCentralPubMedGoogle Scholar
  48. 48.
    Tu Z, Li H, Ma Y, Tang B, Tian J, Akers W, Achilefu S, Gu Y (2012) The enhanced antiproliferative response to combined treatment of trichostatin A with raloxifene in MCF-7 breast cancer cells and its relevance to estrogen receptor β expression. Mol Cell Biochem 366:111–122. doi: 10.1007/s11010-012-1288-9 PubMedCrossRefGoogle Scholar
  49. 49.
    Pitta CA, Papageorgis P, Charalambous C, Constantinou AI (2013) Reversal of ER-β silencing by chromatin modifying agents overrides acquired tamoxifen resistance. Cancer Lett 337:167–176. doi: 10.1016/j.canlet.2013.05.031 PubMedCrossRefGoogle Scholar
  50. 50.
    Hostetter CL, Licata LA, Keen JC (2009) Timing is everything: Order of administration of 5-aza 2′ deoxycytidine, trichostatin A and tamoxifen changes estrogen receptor mRNA expression and cell sensitivity. Cancer Lett 275:178–184. doi: 10.1016/j.canlet.2008.10.005 PubMedCrossRefGoogle Scholar
  51. 51.
    Fan J, Yin W-J, Lu J-S, Wang L, Wu J, Wu F-Y, Di G-H, Shen Z-Z, Shao Z-M (2008) ER alpha negative breast cancer cells restore response to endocrine therapy by combination treatment with both HDAC inhibitor and DNMT inhibitor. J Cancer Res Clin Oncol 134:883–890. doi: 10.1007/s00432-008-0354-x PubMedCrossRefGoogle Scholar
  52. 52.
    Hung W-C (2012) Inhibition of lymphangiogenic factor VEGF-C expression and production by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in breast cancer cells. Oncol Rep. doi: 10.3892/or.2012.2188 Google Scholar
  53. 53.
    Chiu H-W, Yeh Y-L, Wang Y-C, Huang W-J, Chen Y-A, Chiou Y-S, Ho S-Y, Lin P, Wang Y-J (2013) Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, enhances radiosensitivity and suppresses lung metastasis in breast cancer in vitro and in vivo. PLoS ONE 8:e76340. doi: 10.1371/journal.pone.0076340 PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Eades G, Yang M, Yao Y, Zhang Y, Zhou Q (2011) miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells. J Biol Chem 286:40725–40733. doi: 10.1074/jbc.M111.275495 PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Bellarosa D, Bressan A, Bigioni M, Parlani M, Maggi CA, Binaschi M (2012) SAHA/Vorinostat induces the expression of the CD137 receptor/ligand system and enhances apoptosis mediated by soluble CD137 receptor in a human breast cancer cell line. Int J Oncol 41:1486–1494. doi: 10.3892/ijo.2012.1551 PubMedGoogle Scholar
  56. 56.
    Lu S, Labhasetwar V (2013) Drug resistant breast cancer cell line displays cancer stem cell phenotype and responds sensitively to epigenetic drug SAHA. Drug Deliv Transl Res 3:183–194. doi: 10.1007/s13346-012-0113-z PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Rao R, Balusu R, Fiskus W, Mudunuru U, Venkannagari S, Chauhan L, Smith JE, Hembruff SL, Ha K, Atadja P, Bhalla KN (2012) Combination of pan-histone deacetylase inhibitor and autophagy inhibitor exerts superior efficacy against triple-negative human breast cancer cells. Mol Cancer Ther 11:973–983. doi: 10.1158/1535-7163.MCT-11-0979 PubMedCrossRefGoogle Scholar
  58. 58.
    Huang Y, Vasilatos SN, Boric L, Shaw PG, Davidson NE (2012) Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Res Treat 131:777–789. doi: 10.1007/s10549-011-1480-8 PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Vasilatos SN, Katz TA, Oesterreich S, Wan Y, Davidson NE, Huang Y (2013) Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. Carcinogenesis 34:1196–1207. doi: 10.1093/carcin/bgt033 PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Fortunati N, Catalano MG, Marano F, Mugoni V, Pugliese M, Bosco O, Mainini F, Boccuzzi G (2010) The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS). Breast Cancer Res Treat 124:667–675. doi: 10.1007/s10549-010-0789-z PubMedCrossRefGoogle Scholar
  61. 61.
    Tate CR, Rhodes LV, Segar HC, Driver JL, Pounder FN, Burow ME, Collins-Burow BM (2012) Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat. Breast Cancer Res 14:R79. doi: 10.1186/bcr3192 PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Chen S, Ye J, Kijima I, Evans D (2010) The HDAC inhibitor LBH589 (panobinostat) is an inhibitory modulator of aromatase gene expression. Proc Natl Acad Sci 107:11032–11037. doi: 10.1073/pnas.1000917107 PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Wang S, Huang J, Lyu H, Lee C-K, Tan J, Wang J, Liu B (2013) Functional cooperation of miR-125a, miR-125b, and miR-205 in entinostat-induced downregulation of erbB2/erbB3 and apoptosis in breast cancer cells. Cell Death Dis 4:e556. doi: 10.1038/cddis.2013.79 PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Huang X, Wang S, Lee C-K, Yang X, Liu B (2011) HDAC inhibitor SNDX-275 enhances efficacy of trastuzumab in erbB2-overexpressing breast cancer cells and exhibits potential to overcome trastuzumab resistance. Cancer Lett 307:72–79. doi: 10.1016/j.canlet.2011.03.019 PubMedCrossRefGoogle Scholar
  65. 65.
    Sabnis GJ, Goloubeva O, Chumsri S, Nguyen N, Sukumar S, Brodie AMH (2011) Functional activation of the estrogen receptor-α and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole. Cancer Res 71:1893–1903. doi: 10.1158/0008-5472.CAN-10-2458 PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Chumsri S, Sabnis GJ, Howes T, Brodie AMH (2011) Aromatase inhibitors and xenograft studies. Steroids 76:730–735. doi: 10.1016/j.steroids.2011.02.033 PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Srivastava RK, Kurzrock R, Shankar S (2010) MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo. Mol Cancer Ther 9:3254–3266. doi: 10.1158/1535-7163.MCT-10-0582 PubMedCrossRefGoogle Scholar
  68. 68.
    Olsen CM, Meussen-Elholm ETM, Røste LS, Taubøll E (2004) Antiepileptic drugs inhibit cell growth in the human breast cancer cell line MCF7. Mol Cell Endocrinol 213:173–179. doi: 10.1016/j.mce.2003.10.032 PubMedCrossRefGoogle Scholar
  69. 69.
    Hodges-Gallagher L, Valentine CD, Bader SE, Kushner PJ (2007) Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells. Breast Cancer Res Treat 105:297–309. doi: 10.1007/s10549-006-9459-6 PubMedCrossRefGoogle Scholar
  70. 70.
    Rodríguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17:330–339. doi: 10.1038/nm.2305 PubMedCrossRefGoogle Scholar
  71. 71.
    Vansteenkiste J, Van Cutsem E, Dumez H, Chen C, Ricker JL, Randolph SS, Schöffski P (2008) Early phase II trial of oral Vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New Drugs 26:483–488. doi: 10.1007/s10637-008-9131-6 PubMedCrossRefGoogle Scholar
  72. 72.
    Luu TH, Morgan RJ, Leong L, Lim D, McNamara M, Portnow J, Frankel P, Smith DD, Doroshow JH, Gandara DR, Aparicio A, Somlo G, Wong C (2008) A phase II trial of Vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clin Cancer Res 14:7138–7142. doi: 10.1158/1078-0432.CCR-08-0122 PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Munster PN, Marchion D, Thomas S, Egorin M, Minton S, Springett G, Lee J-H, Simon G, Chiappori A, Sullivan D, Daud A (2009) Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker. Br J Cancer 101:1044–1050. doi: 10.1038/sj.bjc.6605293 PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Ramaswamy B, Fiskus W, Cohen B, Pellegrino C, Hershman DL, Chuang E, Luu T, Somlo G, Goetz M, Swaby R, Shapiro CL, Stearns V, Christos P, Espinoza-Delgado I, Bhalla K, Sparano JA (2011) Phase I–II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo. Breast Cancer Res Treat 132:1063–1072. doi: 10.1007/s10549-011-1928-x PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Munster PN, Thurn KT, Thomas S, Raha P, Lacevic M, Miller A, Melisko M, Ismail-Khan R, Rugo H, Moasser M, Minton SE (2011) A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer 104:1828–1835. doi: 10.1038/bjc.2011.156 PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Stathis A, Hotte SJ, Chen EX, Hirte HW, Oza AM, Moretto P, Webster S, Laughlin A, Stayner L-A, McGill S, Wang L, Zhang W, Espinoza-Delgado I, Holleran JL, Egorin MJ, Siu LL (2011) Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Clin Cancer Res 17:1582–1590. doi: 10.1158/1078-0432.CCR-10-1893 PubMedCrossRefGoogle Scholar
  77. 77.
    Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM, Cruickshank S, Miller KD, Lee MJ, Trepel JB (2013) Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol Off J Am Soc Clin Oncol 31:2128–2135. doi: 10.1200/JCO.2012.43.7251 CrossRefGoogle Scholar
  78. 78.
    Stearns V (2011) NCT01349959. Azacitidine and entinostat in treating patients with advanced breast cancer. https://clinicaltrials.gov
  79. 79.
    Finn R (2008) NCT00777335. Study of panobinostat monotherapy in women with v-ERB-B2 avian erythroblastic leukemia viral oncogene homolog 2 (HER2) positive locally recurrent or metastatic breast cancer. https://clinicaltrials.gov
  80. 80.
    Jones SF, Infante JR, Thompson DS, Mohyuddin A, Bendell JC, Yardley DA, Burris HA 3rd (2012) A phase I trial of oral administration of panobinostat in combination with paclitaxel and carboplatin in patients with solid tumors. Cancer Chemother Pharmacol 70:471–475. doi: 10.1007/s00280-012-1931-x PubMedCrossRefGoogle Scholar
  81. 81.
    O’Regan R (2010) NCT01194908. Re-expression of ER in triple negative breast cancers. https://clinicaltrials.gov
  82. 82.
    Munster P (2009) NCT01010854. Valproic acid in combination with FEC100 for primary therapy in patients with breast cancer (VPA-FEC100). https://clinicaltrials.gov
  83. 83.
    Münster P, Marchion D, Bicaku E, Schmitt M, Lee JH, DeConti R, Simon G, Fishman M, Minton S, Garrett C, Chiappori A, Lush R, Sullivan D, Daud A (2007) Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study. J Clin Oncol Off J Am Soc Clin Oncol 25:1979–1985. doi:10.1200/JCO.2006.08.6165 10.1200/JCO.2006.08.6165 CrossRefGoogle Scholar
  84. 84.
    (2010) NCT01171924. A phase Ib expansion study investigating the safety, efficacy, and pharmacokinetics of intravenous CUDC-101 in subjects with advanced head and neck, gastric, breast, liver and non-small cell lung cancer tumors. https://clinicaltrials.gov
  85. 85.
    Lai C-J, Bao R, Tao X, Wang J, Atoyan R, Qu H, Wang D-G, Yin L, Samson M, Forrester J, Zifcak B, Xu G-X, DellaRocca S, Zhai H-X, Cai X, Munger WE, Keegan M, Pepicelli CV, Qian C (2010) CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res 70:3647–3656. doi: 10.1158/0008-5472.CAN-09-3360 PubMedCrossRefGoogle Scholar
  86. 86.
    Hervouet E, Vallette FM, Cartron P-F (2009) Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenetics 4:487–499PubMedCrossRefGoogle Scholar
  87. 87.
    Khan SI, Aumsuwan P, Khan IA, Walker LA, Dasmahapatra AK (2012) Epigenetic events associated with breast cancer and their prevention by dietary components targeting the epigenome. Chem Res Toxicol 25:61–73. doi: 10.1021/tx200378c PubMedCrossRefGoogle Scholar
  88. 88.
    Mirza S, Sharma G, Parshad R, Gupta SD, Pandya P, Ralhan R (2013) Expression of DNA methyltransferases in breast cancer patients and to analyze the effect of natural compounds on dna methyltransferases and associated proteins. J Breast Cancer 16:23–31. doi: 10.4048/jbc.2013.16.1.23 PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Jiang M, Huang O, Zhang X, Xie Z, Shen A, Liu H, Geng M, Shen K (2013) Curcumin induces cell death and restores tamoxifen sensitivity in the antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9. Molecules 18:701–720. doi: 10.3390/molecules18010701 PubMedCrossRefGoogle Scholar
  90. 90.
    Li Y, Chen H, Hardy TM, Tollefsbol TO (2013) Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein. PLoS One 8:e54369. doi: 10.1371/journal.pone.0054369 PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Montenegro MF, Sáez-Ayala M, Piñero-Madrona A, Cabezas-Herrera J, Rodríguez-López JN (2012) Reactivation of the tumour suppressor RASSF1A in breast cancer by simultaneous targeting of DNA and E2F1 methylation. PLoS One 7:e52231. doi: 10.1371/journal.pone.0052231 PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Liu H (2012) MicroRNAs in breast cancer initiation and progression. Cell Mol Life Sci 69:3587–3599. doi: 10.1007/s00018-012-1128-9 PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Rivenbark AG, Stolzenburg S, Beltran AS, Yuan X, Rots MG, Strahl BD, Blancafort P (2012) Epigenetic reprogramming of cancer cells via targeted DNA methylation. Epigenetics 7:350–360. doi: 10.4161/epi.19507 PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Beltran AS, Russo A, Lara H, Fan C, Lizardi PM, Blancafort P (2011) Suppression of breast tumor growth and metastasis by an engineered transcription factor. PLoS ONE 6:e24595. doi: 10.1371/journal.pone.0024595 PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Holliday DL, Speirs V (2011) Choosing the right cell line for breast cancer research. Breast Cancer Res 13:215. doi: 10.1186/bcr2889 PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe J-P, Tong F, Speed T, Spellman PT, DeVries S, Lapuk A, Wang NJ, Kuo W-L, Stilwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gazdar A, Gray JW (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10:515–527. doi: 10.1016/j.ccr.2006.10.008 PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51. doi: 10.1038/nrc1779 PubMedCrossRefGoogle Scholar
  98. 98.
    Novartis Pharmaceuticals (2008) NCT00788931. A trial l of panobinostat given in combination with trastuzumab and paclitaxel in adult female patients with HER2 positive metastatic breast cancer. https://clinicaltrials.gov
  99. 99.
    Burris HA (2008) NCT00632489. LBH589 in combination with capecitabine plus/minus (±) lapatinib in breast cancer patients. https://clinicaltrials.gov
  100. 100.
    Tan W (2010) NCT01105312. Panobinostat and letrozole in treating patients with metastatic breast cancer. In: clinicaltrials.orgGoogle Scholar
  101. 101.
    Pharmaceuticals N (2007) NCT00567879. A trial of panobinostat and trastuzumab for adult female patients with HER2 positive metastatic breast cancer whose disease has progressed on or after trastuzumab. https://clinicaltrials.gov
  102. 102.
    Hurvitz S (2008) NCT00777049. Study of panobinostat monotherapy in women with HER2 negative locally recurrent or metastatic breast cancer. https://clinicaltrials.gov
  103. 103.
    Collins-Burow B (2009) NCT00993642. ERB-B4 after treatment with HDAC inhibitor in ER + tamoxifen refractory breast cancer. https://clinicaltrials.gov
  104. 104.
    Kummar S (2001) NCT00020579. MS-275 in treating patients with advanced solid tumors or lymphoma. https://clinicaltrials.gov
  105. 105.
    Ueno N (2011) NCT01434303. Entinostat, lapatinib ditosylate and trastuzumab in patients with locally recurrent or distant relapsed metastatic breast cancer previously treated with trastuzumab only. https://clinicaltrials.gov
  106. 106.
    McCulloch W (2012) NCT01594398. Study to assess food effect on pharmacokinetics of entinostat in subjects with breast cancer or non-small cell lung cancer (ENCORE110). https://clinicaltrials.gov
  107. 107.
    Yardley D (2008) NCT00676663. Study to evaluate exemestane with and without SNDX-275 in treatment of postmenopausal women with advanced breast cancer (ENCORE301). https://clinicaltrials.gov
  108. 108.
    Pharmaceuticals S (2009) NCT00828854. A phase 2, multicenter study of the effect of the addition of SNDX-275 to continued aromatase inhibitor (AI) therapy in postmenopausal women With ER + breast cancer whose disease is progressing. https://clinicaltrials.gov
  109. 109.
    Chumsri S (2010) NCT01234532. Entinostat and anastrozole in treating postmenopausal women with triple-negative breast cancer that can be removed by surgery. https://clinicaltrials.gov
  110. 110.
    Linden H (2012) NCT01720602. Vorinostat in treating patients with stage IV breast cancer receiving hormone therapy. https://clinicaltrials.gov
  111. 111.
    Linden H (2010) NCT01153672. Vorinostat in treating patients with stage IV breast cancer receiving aromatase inhibitor therapy. https://clinicaltrials.gov
  112. 112.
    Luu T (2010) NCT01084057. Ixabepilone and vorinostat in treating patients with metastatic breast cancer. https://clinicaltrials.gov
  113. 113.
    Esserman L (2008) NCT00788112. orinostat in treating women with ductal carcinoma in situ of the breast. https://clinicaltrials.gov
  114. 114.
    Sparano J (2006) NCT00368875. Vorinostat, paclitaxel, and bevacizumab in treating patients with metastatic breast cancer and/or breast cancer that has recurred in the chest wall and cannot be removed by surgery. https://clinicaltrials.gov
  115. 115.
    Swaby R (2005) NCT00258349. Vorinostat and trastuzumab in treating patients with metastatic or locally recurrent breast cancer. https://clinicaltrials.gov
  116. 116.
    Stearns V (2005) NCT00262834. Vorinostat in treating women who are undergoing surgery for newly diagnosed stage I, stage II, or stage III breast cancer. https://clinicaltrials.gov
  117. 117.
    Stearns V (2008) NCT00616967. Carboplatin and paclitaxel albumin-stabilized nanoparticle formulation with or without vorinostat in treating women with breast cancer that can be removed by surgery. https://clinicaltrials.gov
  118. 118.
    Luu T (2005) NCT00132002. Suberoylanilide hydroxamic acid in treating patients with progressive stage IV breast cancer. https://clinicaltrials.gov
  119. 119.
    Minton S (2006) NCT00365599. Phase II trial of SAHA & tamoxifen for patients with breast cancer. https://clinicaltrials.gov
  120. 120.
    Chumsri S (2010) NCT01118975. Vorinostat and lapatinib in advanced solid tumors and advanced breast cancer to evaluate response and biomarkers. https://clinicaltrials.gov

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Aurore Claude-Taupin
    • 1
  • Michael Boyer-Guittaut
    • 1
  • Régis Delage-Mourroux
    • 1
  • Eric Hervouet
    • 1
    Email author
  1. 1.Laboratoire de Biochimie, Equipe EA3922. Estrogènes, expression génique et pathologies du système nerveux central, Batiment DF, UFR-STUniversité de Franche-ComtéBesançon CedexFrance

Personalised recommendations