Abstract
Epigenetics refers to alterations in gene expression due to differential histone modifications and DNA methylation at promoter sites of genes. Epigenetic alterations are reversible and are heritable during somatic cell division, but do not involve changes in nucleotide sequence. Epigenetic regulation plays a critical role in normal growth and embryonic development by controlling transcriptional activities of several genes. In last two decades, these modifications have been well recognized to be involved in tumor initiation and progression, which has motivated many investigators to incorporate this novel field in cancer drug development. Recently, growing number of epigenetic changes have been reported that are involved in the regulations of genes involved in breast tumor growth and metastasis. Drugs possessing epigenetic modulatory activities known as epi-drugs, mainly the inhibitors of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Some of these drugs are undergoing different clinical trials for breast cancer treatment. Several phytochemicals such as green tea polyphenols, curcumin, genistein, resveratrol and sulforaphane have also been shown to alter epigenetic modifications in multiple cancer types including breast cancer. In this chapter, we summarize the role of epigenetic changes in breast cancer progression and metastasis. We have also discussed about various epigenetic modulators possessing chemopreventive and therapeutic efficacy against breast cancer with future perspectives.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aapola U, Kawasaki K, Scott HS et al (2000) Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 65:293–298
Ai L, Tao Q, Zhong S, Fields CR, Kim WJ, Lee MW, Cui Y, Brown KD, Robertson KD (2006) Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer. Carcinogenesis 27:1341–1348
Ashraf N et al (2006) Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer 95(8):1056–1061
Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6(2):107–116
Benetti R, Gonzalo S, Jaco I et al (2008) A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat Struct Mol Biol 15:268–279
Benevolenskaya EV, Islam AB, Ahsan H et al (2016) DNA methylation and hormone receptor status in breast cancer. Clin Epigenetics 8:17
Berdasco M, Ropero S, Setien F, Fraga MF, Lapunzina P, Losson R, Alaminos M, Cheung NK, Rahman N, Esteller M (2009) Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. Proc Natl Acad Sci U S A 106:21830–21835
Bernstein BE, Kamal M, Lindblad-Toh K et al (2005) Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120:169–181
Bettuzzi S et al (2006) Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 66(2):1234–1240
Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE (2006) Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 8:R38
Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784
Bracken AP, Helin K (2009) Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer 9(11):773–784
Brooks J, Cairns P, Zeleniuch-Jacquotte A (2009) Promoter methylation and the detection of breast cancer. Cancer Causes Control 20:1539–1550
Byrd JC, Marcucci G, Parthun MR et al (2005) A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 105:959–967
Calin GA (2009) MicroRNAs and cancer: what we know and what we still have to learn. Genome Med 1:78
Chedin F, Lieber MR, Hsieh CL (2002) The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc Natl Acad Sci U S A 99:16916–16921
Chen S, Wang Y, Zhou W et al (2014) Identifying novel selective non-nucleoside DNA methyltransferase 1 inhibitors through docking-based virtual screening. J Med Chem 57:9028–9041
Cheng AL et al (2001) Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21(4B):2895–2900
Cho YH, Yazici H, Wu HC, Terry MB, Gonzalez K, Qu M, Dalay N, Santella RM (2010) Aberrant promoter hypermethylation and genomic hypomethylation in tumor, adjacent normal tissues and blood from breast cancer patients. Anticancer Res 30:2489–2496
Dhillon N et al (2008) Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14(14):4491–4499
Dong A, Yoder JA, Zhang X, Zhou L, Bestor TH, Cheng X (2001) Structure of human DNMT2, an enigmatic DNA methyltransferase homolog that displays denaturant-resistant binding to DNA. Nucleic Acids Res 29:439–448
Dulaimi E, Hillinck J, Ibanez de Caceres I, Al-Saleem T, Cairns P (2004) Tumor suppressor gene promoter hypermethylation in serum of breast cancer patients. Clin Cancer Res 10:6189–6193
Duong V, Bret C, Altucci L et al (2008) Specific activity of class II histone deacetylases in human breast cancer cells. Mol Cancer Res 6:1908–1919
Eden A, Gaudet F, Waghmare A, Jaenisch R (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300:455
Eiriksdottir G, Johannesdottir G, Ingvarsson S et al (1998) Mapping loss of heterozygosity at chromosome 13q: loss at 13q12-q13 is associated with breast tumour progression and poor prognosis. Eur J Cancer 34:2076–2081
Elsheikh SE, Green AR, Rakha EA et al (2009) Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res 69:3802–3809
Esteller M (2000) Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. Eur J Cancer 36(18):2294–2300
Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8(4):286–298
Esteller M et al (2001) DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 10(26):3001–3007
Fang F, Turcan S, Rimner A et al (2011) Breast cancer methylomes establish an epigenomic foundation for metastasis. Sci Transl Med 3:75ra25
Ferguson-Smith AC, Surani MA (2001) Imprinting and the epigenetic asymmetry between parental genomes. Science 293:1086–1089
Ferrari R, Pellegrini M, Horwitz GA, Xie W, Berk AJ, Kurdistani SK (2008) Epigenetic reprogramming by adenovirus e1a. Science 321:1086–1088
Foss F, Advani R, Duvic M et al (2015) A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol 168:811–819
Fraga MF et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37(4):391–400
Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283:1026–1033
Garcia JS, Jain N, Godley LA (2010) An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes. Oncol Targets Ther 3:1–13
Gayther SA, Batley SJ, Linger L et al (2000) Mutations truncating the EP300 acetylase in human cancers. Nat Genet 24:300–303
Girault I, Tozlu S, Lidereau R, Bièche I (2003) Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Clin Cancer Res 9:4415–4422
Gorrini C et al (2007) Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448(7157):1063–1067
Gros C, Fleury L, Nahoum V et al (2015) New insights on the mechanism of quinoline-based DNA methyltransferase inhibitors. J Biol Chem 290:6293–6302
Guo D, Myrdal PB, Karlage KL, O’Connell SP, Wissinger TJ, Tabibi SE, Yalkowsky SH (2010) Stability of 5-fluoro-2′-deoxycytidine and tetrahydrouridine in combination. AAPS PharmSciTech 11:247–252
Hon GC, Hawkins RD, Caballero OL et al (2012) Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res 22:246–258
Horton JR, Engstrom A, Zoeller EL, Liu X, Shanks JR, Zhang X, Johns MA, Vertino PM, Fu H, Cheng X (2016) Characterization of a linked Jumonji domain of the KDM5/JARID1 family of histone H3 lysine 4 demethylases. J Biol Chem 291:2631–2646
Hosseini A, Ghorbani A (2015) Cancer therapy with phytochemicals: evidence from clinical studies. Avicenna J Phytomed 5(2):84–97
Huang Q, Gumireddy K, Schrier M et al (2008) The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol 10:202–210
Iorio MV, Casalini P, Piovan C, Braccioli L, Tagliabue E (2011) Breast cancer and microRNAs: therapeutic impact. Breast 20(Suppl 3):S63–S70
Iyer NG, Ozdag H, Caldas C (2004) p300/CBP and cancer. Oncogene 23:4225–4231
Jackson K, Yu MC, Arakawa K, Fiala E, Youn B, Fiegl H, Müller-Holzner E, Widschwendter M, Ehrlich M (2004) DNA hypomethylation is prevalent even in low-grade breast cancers. Cancer Biol Ther 3:1225–1231
Jenuwein T, Allis CD (2001) Translating the histone code. Science 293(5532):1074–1080
Jin Z, Tamura G, Tsuchiya T, Sakata K, Kashiwaba M, Osakabe M, Motoyama T (2001) Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers. Br J Cancer 85:69–73
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647
Jones PA (2002) DNA methylation and cancer. Oncogene 21:5358–5360
Kim VN (2005) MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 6:376–385
Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ (1998) Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396:84–88
Knudson AG (2000) Chasing the cancer demon. Annu Rev Genet 34:1–19
Kotecha R, Takami A, Espinoza JL (2016) Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence. Oncotarget 7(32):52517–52529
Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705
Kunju LP, Cookingham C, Toy KA, Chen W, Sabel MS, Kleer CG (2011) EZH2 and ALDH-1 mark breast epithelium at risk for breast cancer development. Mod Pathol 24:786–793
Lehmann U, Hasemeier B, Christgen M, Müller M, Römermann D, Länger F, Kreipe H (2008) Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer. J Pathol 214:17–24
Levi F et al (2005) Resveratrol and breast cancer risk. Eur J Cancer Prev 14(2):139–142
Lin YW, Sheu JC, Liu LY, Chen CH, Lee HS, Huang GT, Wang JT, Lee PH, Lu FJ (1999) Loss of heterozygosity at chromosome 13q in hepatocellular carcinoma: identification of three independent regions. Eur J Cancer 35:1730–1734
Lo PK, Sukumar S (2008) Epigenomics and breast cancer. Pharmacogenomics 9:1879–1902
Lo PK, Mehrotra J, D’Costa A, Fackler MJ, Garrett-Mayer E, Argani P, Sukumar S (2006) Epigenetic suppression of secreted frizzled related protein 1 (SFRP1) expression in human breast cancer. Cancer Biol Ther 5:281–286
Ma L, Teruya-Feldstein J, Weinberg RA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449:682–688
Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315:1576–1579
Mertens-Talcott SU et al (2007) The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res 67(22):11001–11011
Müller BM, Jana L, Kasajima A, Lehmann A, Prinzler J, Budczies J, Winzer KJ, Dietel M, Weichert W, Denkert C (2013) Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer--overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. BMC Cancer 13:215
Nakamura K, Nakabayashi K, Htet Aung K, Aizawa K, Hori N, Yamauchi J, Hata K, Tanoue A (2015) DNA methyltransferase inhibitor zebularine induces human cholangiocarcinoma cell death through alteration of DNA methylation status. PLoS One 10:e0120545
Newman EM, Morgan RJ, Kummar S et al (2015) A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine, administered with tetrahydrouridine. Cancer Chemother Pharmacol 75:537–546
Norouzi S et al (2018) Curcumin as an adjunct therapy and microRNA modulator in breast cancer. Curr Pharm Des 24(2):171–177
O’Connor OA (2006) Pralatrexate: an emerging new agent with activity in T-cell lymphomas. Curr Opin Oncol 18(6):591–597
O’Connor OA, Horwitz S, Masszi T et al (2015) Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol 33:2492–2499
O’Day E, Lal A (2010) MicroRNAs and their target gene networks in breast cancer. Breast Cancer Res 12(2):201
Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257
Park SY, Jun JA, Jeong KJ, Heo HJ, Sohn JS, Lee HY, Park CG, Kang J (2011) Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer. Oncol Rep 25:1677–1681
Piekarz RL, Frye R, Turner M et al (2009) Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27:5410–5417
Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN, Herman JG, Baylin SB (2006) Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet 2:e40
Rasti M et al (2005) Recruitment of CBP/p300, TATA-binding protein, and S8 to distinct regions at the N terminus of adenovirus E1A. J Virol 79(9):5594–5605
Rauscher GH, Kresovich JK, Poulin M et al (2015) Exploring DNA methylation changes in promoter, intragenic, and intergenic regions as early and late events in breast cancer formation. BMC Cancer 15:816
Reik W, Lewis A (2005) Co-evolution of X-chromosome inactivation and imprinting in mammals. Nat Rev Genet 6(5):403–410
Reynolds PA, Sigaroudinia M, Zardo G, Wilson MB, Benton GM, Miller CJ, Hong C, Fridlyand J, Costello JF, Tlsty TD (2006) Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J Biol Chem 281:24790–24802
Richardson BC (2002) Role of DNA methylation in the regulation of cell function: autoimmunity, aging and cancer. J Nutr 132:2401S–2405S
Roll JD, Rivenbark AG, Jones WD, Coleman WB (2008) DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines. Mol Cancer 7:15
Ropero S, Fraga MF, Ballestar E et al (2006) A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nat Genet 38:566–569
Ruike Y, Imanaka Y, Sato F, Shimizu K, Tsujimoto G (2010) Genome-wide analysis of aberrant methylation in human breast cancer cells using methyl-DNA immunoprecipitation combined with high-throughput sequencing. BMC Genomics 11:137
Saunders LR, Verdin E (2007) Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 26(37):5489–5504
Schneider R, Bannister AJ, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T (2004) Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nat Cell Biol 6:73–77
Schübeler D, MacAlpine DM, Scalzo D et al (2004) The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev 18:1263–1271
Schultz J et al (2008) MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth. Cell Res 18(5):549–557
Shukla V, Coumoul X, Lahusen T et al (2010) BRCA1 affects global DNA methylation through regulation of DNMT1. Cell Res 20:1201–1215
Shukla S, Khan S, Tollefsbol TO et al (2013) Genetics and epigenetics of lung cancer: mechanisms and future perspectives. Curr Cancer Ther Rev 9:97–110
Shukla S, Meeran SM, Katiyar SK (2014) Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention. Cancer Lett 355(1):9–17
Silva J, Silva JM, Domínguez G, García JM, Cantos B, Rodríguez R, Larrondo FJ, Provencio M, España P, Bonilla F (2003) Concomitant expression of p16INK4a and p14ARF in primary breast cancer and analysis of inactivation mechanisms. J Pathol 199:289–297
Sinkkonen L, Hugenschmidt T, Berninger P, Gaidatzis D, Mohn F, Artus-Revel CG, Zavolan M, Svoboda P, Filipowicz W (2008) MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nat Struct Mol Biol 15:259–267
Song FF, Xia LL, Ji P et al (2015) Human dCTP pyrophosphatase 1 promotes breast cancer cell growth and stemness through the modulation on 5-methyl-dCTP metabolism and global hypomethylation. Oncogene 4:e159
Storka A et al (2015) Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans. Int J Clin Pharmacol Ther 53(1):54–65
Tajima S, Suetake I (1998) Regulation and function of DNA methylation in vertebrates. J Biochem 123(6):993–999
Takai D, Jones PA (2002) Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 99(6):3740–3745
Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massagué J (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451:147–152
Tlsty TD et al (2004) Genetic and epigenetic changes in mammary epithelial cells may mimic early events in carcinogenesis. J Mammary Gland Biol Neoplasia 9(3):263–274
Veeck J, Esteller M (2010) Breast cancer epigenetics: from DNA methylation to microRNAs. J Mammary Gland Biol Neoplasia 15(1):5–17
Ventura A, Young AG, Winslow MM et al (2008) Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132:875–886
Wang GG, Allis CD, Chi P (2007) Chromatin remodeling and cancer, Part I: Covalent histone modifications. Trends Mol Med 13:363–372
Widschwendter M, Jones PA (2002) DNA methylation and breast carcinogenesis. Oncogene 21(35):5462–5482
Xu X, Gammon MD, Hernandez-Vargas H, Herceg Z, Wetmur JG, Teitelbaum SL, Bradshaw PT, Neugut AI, Santella RM, Chen J (2012) DNA methylation in peripheral blood measured by LUMA is associated with breast cancer in a population-based study. FASEB J 26:2657–2666
Yang PM, Lin YT, Shun CT, Lin SH, Wei TT, Chuang SH, Wu MS, Chen CC (2013) Zebularine inhibits tumorigenesis and stemness of colorectal cancer via p53-dependent endoplasmic reticulum stress. Sci Rep 3:3219
Zhang L, Coukos G (2006) MicroRNAs: a new insight into cancer genome. Cell Cycle 5:2216–2219
Zhu W et al (2012) Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr Cancer 64(3):393–400
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Shukla, S., Penta, D., Mondal, P., Meeran, S.M. (2019). Epigenetics of Breast Cancer: Clinical Status of Epi-drugs and Phytochemicals. In: Ahmad, A. (eds) Breast Cancer Metastasis and Drug Resistance. Advances in Experimental Medicine and Biology, vol 1152. Springer, Cham. https://doi.org/10.1007/978-3-030-20301-6_16
Download citation
DOI: https://doi.org/10.1007/978-3-030-20301-6_16
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-20300-9
Online ISBN: 978-3-030-20301-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)