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. 2015;1238:425-66.
doi: 10.1007/978-1-4939-1804-1_23.

Epigenetics in Breast and Prostate Cancer

Free PMC article

Epigenetics in Breast and Prostate Cancer

Yanyuan Wu et al. Methods Mol Biol. .
Free PMC article


Most recent investigations into cancer etiology have identified a key role played by epigenetics. Specifically, aberrant DNA and histone modifications which silence tumor suppressor genes or promote oncogenes have been demonstrated in multiple cancer models. While the role of epigenetics in several solid tumor cancers such as colorectal cancer are well established, there is emerging evidence that epigenetics also plays a critical role in breast and prostate cancer. In breast cancer, DNA methylation profiles have been linked to hormone receptor status and tumor progression. Similarly in prostate cancer, epigenetic patterns have been associated with androgen receptor status and response to therapy. The regulation of key receptor pathways and activities which affect clinical therapy treatment options by epigenetics renders this field high priority for elucidating mechanisms and potential targets. A new set of methylation arrays are now available to screen epigenetic changes and provide the cutting-edge tools needed to perform such investigations. The role of nutritional interventions affecting epigenetic changes particularly holds promise. Ultimately, determining the causes and outcomes from epigenetic changes will inform translational applications for utilization as biomarkers for risk and prognosis as well as candidates for therapy.


Figure 1
Figure 1
Assessment of hypermethylation of CpG sites in gene promoters in breast cancer.
Figure 2
Figure 2. Schematic of the MSDK Approach
Reprinted by permission from Macmillan Publishers Ltd: [Nature Genetics] (37(8):899-905), copyright (2005).
Figure 3
Figure 3. Methylation Clustering by Subtype
Figure 3A. Hierarchical clustering of gene methylation. Heatmap shows relative methylations levels (red, more methylated; green, less methylated). Clustering resulted in three clusters: Cluster 1 (Luminal B), Cluster 2 (Luminal A), and Cluster 3 (Basal-Like). Adapted from [42]. Figure 3B. Boxplot stratified by subtype for methylation frequencies of the 196 subtype- associated CpGs. CpGs represented in the plot are more frequently methylated in Luminal B tumors and less methylated in basal-like tumors. P-value was calculated using analysis of variance. The number of tumors in each subtype is shown at the top axis. Adapted from [42].
Figure 4
Figure 4. Schematic of epigenetic modifications that regulate chromatin organization and gene expression
Strands of DNA are wrapped around (A) Schematic of epigenetic modifications. Strands of DNA are wrapped around histone octamers, forming nucleosomes, which organize chromatin. Reversible and site-specific histone modifications occur at multiple sites through acetylation, methylation and phosphorylation. DNA methylation occurs at 5-position of cytosine residues in a reaction catalyzed by DNA methyltransferases (DNMTs). Together, these modifications provide a unique epigenetic signature that regulates chromatin organization and gene expression. Adapted from Luong P., Basic Principles of Genetics [Connexions Web site]. March 2, 2014. Available at:
Figure 5
Figure 5. Principles of Chromatin Immunoprecipitation assay (ChiP)
Reprinted by permission from Macmillan Publishers Ltd: [Nature Reviews Cancer] (Jul;4(7):562-8), copyright (2004).
Figure 6
Figure 6. Example of Histone Acetylation
a. Levels of histone acetylation at specific lysine (K) residues are determined by concurrent reactions of acetylation (AC) and deacetylation, which are mediated by histone acetylases (HATs) and histone deacetylases (HDACs). This histone acetylation is vital for establishing the conformational structure of DNA-chromatin complexes, and subsequently transcriptional gene expression. b. By blocking the deacetylation reaction, HDAC inhibitors change the equilibrium of histone acetylation levels, leading to increased acetylation, chromatin modification to relax confirmation and transcription upregulation. Reprinted by permission from Macmillan Publishers Ltd: [Nat Rev Drug Discov] (Oct;7(10):854-68), copyright (2008).
Figure 7
Figure 7. Workflow of COBRA assay
Reprinted by permission from Oxford University Press: [Nucleic Acids Res] (Jun 15;25(12):2532-4), copyright (1997).
Figure 8
Figure 8. Workflow of COMPARE assay
Reprinted by permission from Oxford University Press: [Nucleic Acids Res] (Feb 9;34(3):e19.), copyright (2006).
Figure 9
Figure 9. Principles of Bisulphite Conversion and Methylation Specific PCR
Standard molecular biology techniques to analyze individual gene loci, such as polymerase chain reaction (PCR) and biological cloning, erase DNA methylation information, leaving the investigator oblivious to the epigenetic information that was present in the original genomic DNA (panel a). 5-methylcytosine residues are indicated as red Ms. The solution to this problem is to modify the DNA in a methylation-dependent way before amplification. This can be achieved either by digestion with a methylation-sensitive restriction enzyme (not shown), or by treating the genomic DNA with sodium bisulphite (panel b), which converts unmethylated cytosines to uracil residues. As a consequence, the converted DNA is no longer self-complementary, and amplification of either the top or bottom DNA strand requires different primers. Priming can be either universal, or methylation specific (panel c). MSP, methylation-specific PCR. Reprinted by permission from Macmillan Publishers Ltd: [Nat Rev Cancer] (Apr;3(4):253-66), copyright (2003).
Figure 10
Figure 10. Dietary inhibitors of DNA methylation
DNA methylation is a biochemical process that is essential for development. Some dietary phytochemicals are reported to inhibit the methylation of cytosine. Hypermethylation of cytidine by DNMTs usually results in transcriptional gene silencing and gene inactivation. Several phytochemicals derived from different food source such as: resveratrol from grapes and berries, curcumin from turmeric, tea phenols from tea leaves, genistein from soybeans, sulforaphane from broccoli, phenethyl isothiocynate from cauliflower, organosulfur compounds from garlic, quercetin from citrus fruits, and lycopene from tomato act as dietary inhibitors of DNA methyltransferases. These compounds also alter gene expression via epigenetic mechanisms. Reprinted from Pharmacol Ther. 2013 Apr;138(1):1-17. Sharmila Shankar, Dhruv Kumar, Rakesh K. Srivastava, Epigenetic modifications by dietary phytochemicals: Implications for personalized nutrition, Pages No.1-17, Copyright (2013), with permission from Elsevier.
Figure 11
Figure 11. Examples of dietary inhibitors of histone modifications
Representation of histonemodifications (acetylation and deacetylation) by the phytochemicals derived from different food sources. Phytochemicals like EGCG, genistein and curcumin play important role in inhibition of histone acetylation by inactivating histone acetyl transferase enzyme. Some other phytochemicals like sulforaphane, curcumin, genistein, phenyl isothiocynate, organosulfur compound, resveratrol and indol-3-carbinol inhibits the deacetylation of relaxed chromatine by inactivating histone deacetylase enzyme. Reprinted from Pharmacol Ther. 2013 Apr;138(1):1-17. Sharmila Shankar, Dhruv Kumar ,Rakesh K. Srivastava, Epigenetic modifications by dietary phytochemicals: Implications for personalized nutrition, Pages No.1-17, Copyright (2013), with permission from Elsevier.

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