Skip to main content
View expanded cover

Cancer Epigenetics pp 487–509Cite as

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

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

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

Protocol
USD   49.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4939-1804-1_25
  • Chapter length: 23 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   149.00
Price excludes VAT (USA)
  • ISBN: 978-1-4939-1804-1
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   199.99
Price excludes VAT (USA)
Hardcover Book
USD   249.99
Price excludes VAT (USA)
Learn about institutional subscriptions
Fig. 1

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

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. 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

    CAS  PubMed  CrossRef  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30. doi:10.3322/caac.21166

    PubMed  CrossRef  Google Scholar 

  3. Antoniou AC, Easton DF (2006) Models of genetic susceptibility to breast cancer. Oncogene 25:5898–5905. doi:10.1038/sj.onc.1209879

    CAS  PubMed  CrossRef  Google Scholar 

  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. Narod S, Lynch H, Conway T, Watson P, Feunteun J, Lenoir G (1993) Increasing incidence of breast cancer in family with BRCA1 mutation. Lancet 341:1101–1102

    CAS  PubMed  CrossRef  Google Scholar 

  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 18:665–677

    CAS  PubMed  Google Scholar 

  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 63:664–673

    CAS  PubMed  Google Scholar 

  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.2013.07.005

    Google Scholar 

  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

    PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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 61:5407–5414

    CAS  PubMed  Google Scholar 

  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

    PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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 48:71–76

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    PubMed Central  PubMed  CrossRef  Google Scholar 

  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 10:266–278

    CAS  PubMed Central  PubMed  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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 61:7025–7029

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  37. Weber J (2002) NCT00030615. Decitabine in treating patients with advanced solid tumors. https://clinicaltrials.gov

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  CrossRef  Google Scholar 

  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. 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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CrossRef  Google Scholar 

  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

    PubMed Central  PubMed  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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. 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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  70. Rodríguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17:330–339. doi:10.1038/nm.2305

    PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  CrossRef  Google Scholar 

  78. Stearns V (2011) NCT01349959. Azacitidine and entinostat in treating patients with advanced breast cancer. https://clinicaltrials.gov

  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. 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

    CAS  PubMed  CrossRef  Google Scholar 

  81. O’Regan R (2010) NCT01194908. Re-expression of ER in triple negative breast cancers. https://clinicaltrials.gov

  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. 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.2006.08.616510.1200/JCO.2006.08.6165

    CrossRef  Google Scholar 

  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. 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

    CAS  PubMed  CrossRef  Google Scholar 

  86. Hervouet E, Vallette FM, Cartron P-F (2009) Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenetics 4:487–499

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  95. Holliday DL, Speirs V (2011) Choosing the right cell line for breast cancer research. Breast Cancer Res 13:215. doi:10.1186/bcr2889

    PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  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

    CAS  PubMed  CrossRef  Google Scholar 

  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. Burris HA (2008) NCT00632489. LBH589 in combination with capecitabine plus/minus (±) lapatinib in breast cancer patients. https://clinicaltrials.gov

  100. Tan W (2010) NCT01105312. Panobinostat and letrozole in treating patients with metastatic breast cancer. In: clinicaltrials.org

    Google Scholar 

  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. Hurvitz S (2008) NCT00777049. Study of panobinostat monotherapy in women with HER2 negative locally recurrent or metastatic breast cancer. https://clinicaltrials.gov

  103. Collins-Burow B (2009) NCT00993642. ERB-B4 after treatment with HDAC inhibitor in ER + tamoxifen refractory breast cancer. https://clinicaltrials.gov

  104. Kummar S (2001) NCT00020579. MS-275 in treating patients with advanced solid tumors or lymphoma. https://clinicaltrials.gov

  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. 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. 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. 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. 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. Linden H (2012) NCT01720602. Vorinostat in treating patients with stage IV breast cancer receiving hormone therapy. https://clinicaltrials.gov

  111. Linden H (2010) NCT01153672. Vorinostat in treating patients with stage IV breast cancer receiving aromatase inhibitor therapy. https://clinicaltrials.gov

  112. Luu T (2010) NCT01084057. Ixabepilone and vorinostat in treating patients with metastatic breast cancer. https://clinicaltrials.gov

  113. Esserman L (2008) NCT00788112. orinostat in treating women with ductal carcinoma in situ of the breast. https://clinicaltrials.gov

  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. Swaby R (2005) NCT00258349. Vorinostat and trastuzumab in treating patients with metastatic or locally recurrent breast cancer. https://clinicaltrials.gov

  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. 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. Luu T (2005) NCT00132002. Suberoylanilide hydroxamic acid in treating patients with progressive stage IV breast cancer. https://clinicaltrials.gov

  119. Minton S (2006) NCT00365599. Phase II trial of SAHA & tamoxifen for patients with breast cancer. https://clinicaltrials.gov

  120. Chumsri S (2010) NCT01118975. Vorinostat and lapatinib in advanced solid tumors and advanced breast cancer to evaluate response and biomarkers. https://clinicaltrials.gov

Download references

Author information

Authors and Affiliations

  1. Laboratoire de Biochimie, Equipe EA3922. Estrogènes, expression génique et pathologies du système nerveux central, Batiment DF, UFR-ST, Université de Franche-Comté, 16, Route de Gray, 25030, Besançon Cedex, France

    Aurore Claude-Taupin, Michael Boyer-Guittaut, Régis Delage-Mourroux & Eric Hervouet

Authors
  1. Aurore Claude-Taupin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Boyer-Guittaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Régis Delage-Mourroux
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric Hervouet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric Hervouet .

Editor information

Editors and Affiliations

  1. National Institutes of Health, Rockville, Maryland, USA

    Mukesh Verma

Rights and permissions

Reprints and Permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this protocol

Cite this protocol

Claude-Taupin, A., Boyer-Guittaut, M., Delage-Mourroux, R., Hervouet, E. (2015). Use of Epigenetic Modulators as a Powerful Adjuvant for Breast Cancer Therapies. In: Verma, M. (eds) Cancer Epigenetics. Methods in Molecular Biology, vol 1238. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1804-1_25

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-1804-1_25

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-1803-4

  • Online ISBN: 978-1-4939-1804-1

  • eBook Packages: Springer Protocols