**1. Introduction**

The term epigenetic was introduced by Conard Waddington in 1942 as a concept of environmental influence in inducing phenotype modification. His work on developmental plasticity states that the environmental influences during development could induce alternative phenotypes from one genotype, one of the clearest examples is polyphenisms in insects. He showed that exposing the pupae of wild type Drosophila melanogaster to heat shock treatment, results in altered wing vein patterns (Waddington, 1952;Waddington, 1959a). Breeding individuals who have been exposed to these environmentally induced changes led to a stable population exhibiting the phenotype without the environmental stimulus. As a result of Waddington's observations of the dynamic interaction between genes and variation in the environment during the plastic phase of development, he described phenotype induction as genetic canalization. Canalization describes the robustness of phenotypes in response to perturbation (Waddington, 1959b;Waddington, 1961;Waddington & Robertson, 1966).

The epigenome controls the genome in both normal and abnormal cellular processes and events (Szyf et al., 2008;Vaissiere et al., 2008). Epigenetic system includes DNA methylation and histone modification and non-coding RNAs, which work cooperatively to control gene expression. As a result, epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer (Hanahan & Weinberg, 2000). Methylation of cytosine bases in DNA provides a layer of epigenetic control in many eukaryotes that has important implications for normal biology and disease. DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting, and chromosome stability.

Additionally, in 1975, DNA methylation was related to the process of X chromosome inactivation in females (Riggs, 1975). Since then, it has been used as a marker for gene silencing and extensively studied as an important mechanism of epigenetic control (Jaenisch & Bird, 2003). For instance, methylation of CpG islands within the imprinted gene promoters ensures transcriptional silencing of the associated parental allele (Nafee et al., 2008). Consistent with these important roles, a growing number of human diseases

Epigenetics and Breast Cancer 293

repeats, are silenced in somatic cells and become reactivated in human cancer (Berdasco & Esteller, 2010). Furthermore, aberrations in DNA methylation patterns of the CpG islands in the promoter regions of tumor-suppressor genes are accepted as being a common feature of human cancer (Esteller, 2008). CpG island promoter hypermethylation affects genes from a wide range of cellular pathways, such as cell cycle, DNA repair, toxic catabolism, cell adherence, apoptosis, and angiogenesis, among others (Esteller, 2008), and may occur at

**Hypermethylation in Breast Cancer**

**Cell adherence**

Fig. 1. Hypothetical model that explain how CpG island promoter hypermethylation. Multiple genes are hypermethylated in breast cancer compared to non-cancerous tissue which are affected genes from a wide range of cellular pathways induced by epigenetic

Therefore, DNA methylation not only participates in cancer but has been found to regulate the histone modifications involved in tumor formation. The presence of certain histone modifications such as H4 R3 me2 is a marker of prostate cancer and increased expression of HDAC6 in breast cancer (Kurdistani, 2007). In addition the prognosis of certain malignancies can be affected by epigenetic status (Sakuma et al., 2007) . In normal cells, repetitive genomic sequences (e.g., centromeric satellite α-DNA and juxtacentromeric satellite DNA) are heavily methylated (Esteller, 2007; Jones & Baylin, 2002). The maintenance of methylation in this repetitive DNA could be important for the protection of chromosomal integrity by preventing chromosomal rearrangements, translocations and gene disruption through the reactivation of transposable elements (Eden et al., 2003; Ehrlich, 2002; Jones & Baylin, 2002). Besides hypermethylation of gene-associated CpG islands, hypomethylation of repetitive genomic DNA has also been identified as a specific feature in

**Toxic** 

Apoptosis

**Angiogenesis Catabolism**

various stages in the development of cancer. (Berdasco & Esteller, 2010).

**DNA Repair**

changes.

**Cell Cycle** 

including cancer have been found to be associated with aberrant DNA methylation. Therefore we will summarize the, in this chapter the current knowledge on mechanisms of epigenetic and its potential application in breast cancers.
