Currently, the worst prognosis
of cancer is breast cancer that has spread or metastasized into other sites
during diagnosis16. To
prevent this metastasis (a spread of cancer to different body parts of where it
had started), millions of lives would be saved. However, the actual progress on
this front means to think about ways in which the metastasis inhibitors are
tested within the clinical trials (S58)16. There are approximately
1.3 million women in the world that are being diagnosed every year with breast
cancer16. This makes it the second common cancer behind lung cancer16.
The emergence of the robust awareness-raising efforts, e.g., “the pink
ribbon campaign” has caused a rise in the public profile of breast cancer16.
Estrogen is the primary hormone in stimulating growth and the development of
The epigenome is described as a group of the
chemical compounds which inform the genomes what to do18. Human genomes have complete assemblies of the
DNA (deoxyribonucleic acids) approximately compromising of 3 billion base pairs
making each of the individuals unique18. The DNA preserves
instructions for the building of proteins which then carry a range of functions
within the cell. Epigenomic compounds usually are attached to the DNA and can
change the functions containing “marked” genomes. The marks don’t
alter sequences of DNA. However, they adjust ways the cells use instructions of
the DNA18. Marks normally are passed from cell to cell when cell
division taking place18. Also passing from a generation to next
Epigenetics is referred as the heritable
changes in the gene expressions, occurring without changes in the nucleotide sequence5.
Changes include the chemical modifications of DNA by DNA methylation or the
changes of proteins, which closely link with the DNA, for example, histones,
which bind and compact the DNA in chromatin packages5. Epigenetic
modifications are enzymatic and as such can be reversed/controlled by
epigenetic inhibitors3. The epigenome is the epigenetic state of a
cell. It is transmitted from the parent to the daughter cells which maintain
the specific epigenotype in the cell lineage15. Gene inactivation or
gene silencing of a tumor suppressor gene can not only be achieved through
mutations. It can be due to a result of inhibition or the translocation of
components of the transcription machinery15. A mechanism which leads
to the inhibition of transcription is gene silencing via epigenetic changes,
e.g., acquisition of promoter methylation which introduces alterations within
the chromatin structure15.
The alterations of epigenetics are an
essential factor in the development of cancers1. Changes in DNA
methylation are a factor in the early events of the progress in tumors. They
have emerged as a hallmark of many cancer types including breast cancer2.
These are also involved in the development of cancer and have a role in its
development and its progression, as exemplified by breast cancer4. Environmental
factors and also lifestyle can cause a change within epigenomes. These include
lifestyle factors and also the environmental which include diet, smoking even
the infectious diseases capable of exposing to an individual to pressures which
prompt the response of chemicals18. Most cancers are due to the
changes within genomes or epigenomes but can be due to both of these.
Alterations within epigenomes are capable of switching genes on or off
involving the cell growth or immune responses. Changes of these can cause the
uncontrolled growth, hallmarks of the cancers or the failure of the immune
system in destroying the tumours18.
Chromatin is a highly ordered structure
containing nucleosomal repeats linked through linker DNA14. The
chromatin complex comprises of histones, DNA, and also the non-histone proteins
that are condensed in the nucleoprotein complex14. There are two
different conformational organizations chromatin normally acquire. These
include the heterochromatin (densely compact and transcription is inactive), and
the euchromatin (decondensed and transcription is active)14.
Histones are small proteins which consist of a glomerular domain. They also
have a charged NH2 terminus (N-terminal tail) which is flexible and
protrudes from the nucleosomes14. The mechanisms for controlling the
transcription of genes are crucial for cell differentiation, cell survival, and
cell proliferation. When deregulated, this process can lead to malignancy
development14. The main determinants of the chromatin structure are
the histone acetylation and the DNA methylation. The chromatin structure is the
main regulator of gene transcription10. Within the nucleus, double-stranded DNA is
compacted and then organized in chromosomes3. DNA normally is
wrapped around the histone protein-complexes to form a large nucleosomal
structure order3. The structure of chromatin is shown in figure 1.
The methylation of DNA happens
within the compact chromatin, influenced by a range of changes within the
histone structures15. The chromatin is the nucleoprotein complex
which compromises of the repeated units as nucleosomes. The single nucleosome
consists of two turns. The first one is the
DNA wrapped around the core histone octamer
which consists of the H1A, H2B, H3 and the H4 histones15. The second
is when genes are involved in DNA repair, cell cycle control, apoptosis
(programmed cell death), angiogenesis and cell-to-cell interaction that are
usually influenced by the hypermethylation of CpG-island promoters15.
These are also involved in the development of cancer15.
Figure 1 | The Structures of
Chromatin adapted from 17. Nucleosomes,
the essential subunits of the chromatin, compromising of the octameric core histones
including the two H2A-H2B dimers and also the H3-H4 tetramer, wrapped on the
two superhelical turns of the DNA leading to the protein having a DNA ratio of
A rise in the acetylation of histones promotes
chromatin structures to open more which is linked to gene activation. The
histone methyltransferases (HMTs) mediate histone methylation8.
Histone methylation events lead to changes in chromatin, alteration of
epigenetic control of gene expressions, e.g. activation or repression of the
genes involved in DNA repair, cell cycle and cancer progression8. The
mechanisms which play a role in altering breast cancer include DNA
hypermethylation, the DNA hypomethylation, the histone hyperacetylation, the
histone demethylation also the histone methylation7. The three DNA
methyltransferases that are active include DNA (cytosine-5)-methyltransferase 1
(cytosine-5)-methyltransferase 3A (DNMT3a), and DNA (cytosine-5-)-methyltransferase
(DNMT3b). Expression of DNMT1 and DNMTb is often upregulated in breast cancer
cells8. The DNMTs interact directly with the histone deacetylases
(HDACs) and with proteins of the methyl-CpG binding domain (MBD) family (a
family of proteins located close to the promoter region to form the repressive
transcription complexes)8. Histone modification and chromatin
structure are affected by the molecular interplay between histone
acetyltransferases (HAT) and the Histone deacetylases (HDAC)8.
The methylation of DNA is usually linked to
normal development and growth. An alteration in the pattern of the DNA
methylation is linked to the development of breast cancer, the metastasis, and
the progression3. Breast cancer is linked to hypermethylation of
tumor suppressor genes and the hypomethylation of oncogenes (genes involved in
causing cancer)3. The epigenetic changes within cancers include the
histone modification, the DNA methylation, and assays. Histones have a role in
shape maintenance of the chromatin structure11. A range of post-translation changes can occur
at the N-terminal tail of histone proteins, leading to a change in conformation
within the chromatin, affecting the transcription of vital genes including
Transcriptional events can be affected by acetylation, methylation or
phosphorylation of target proteins11. HDACs are a member of the
protein complex which is responsible for recruiting transcription factors to
the promoter region of the genes, including tumor suppressor genes11.
The regulation acetylation status is the specific cell cycle regulatory
proteins11. The higher order structure is defined as the assembly of
nucleosomes which assume the reproducibility conformation within the 3D space.
The common chromatin structure is mitotic/meiotic chromosome where DNA is
compacted in 10,000 to 20,000 fold. The metaphase chromosome compromises of the
shapes, the banding patterns and also the locations of the particular genes1.
Transcription factors (TFs) are the main
proteins that are involved in regulating gene transcription. They bind
specifically at the cis-regulatory region of DNA. In breast cancer, the three
main TFs are ER?, FOXA1, and GATA3. TFs contribute to regulating gene
expressions that are linked to estrogen dependent tumor growth2.
Within breast tumors, activated fibroblasts (Cancer-Associated Fibroblasts) are
predominantly of stromal cell type. CAFs also express myofibroblasts9.
CAFs include; ?-smooth muscle actin, vimentin, neuron-glial antigen-2 also
fibroblast specific protein 1, which can be used as markers. A range of growth
factors is then secreted9.
DNA methylation is described as gene silencing
that happens due to DNA methylation at a promoter region of the gene11.
Four bases; adenine, guanine, cytosine, and thymine are the building blocks of
the genetic makeup. A methyl group (–CH3) is added to the pyrimidine
ring of a cytosine, by DNA methyltransferases (DNMTs), to form the
methylcytosine (DNA methylation). These
have a vital role in hyper-methylation of tumor suppressor genes11. DNA methylation processes occur only at the
cytosines preceding guanine within DNA sequences known as CpG dinucleotides11. CpG dinucleotides, existing in the genome,
can be profoundly methylated impeding the gene transcription. When many CpG dinucleotides are found in the
region of gene promoters, these are referred to as CpG islands11. A normal tissue of CpG islands is
unmethylated, for gene transcription to occur. Within cancer, there is abnormal
DNA methylation of CpG islands that obstructs the transcription of vital genes
such as tumor suppressor genes11. The role of DNA methylation in
breast cancer has been well characterized by its epigenetic implications. These usually occur within the cancer cell8.
The hypermethylated CpG dinucleotides that are in the promoter region have a
vital role regulating the individual genes which promote carcinogenesis8.
The mediation of DNA methylation takes place through the action of DNA
methyltransferases (DNMTs). The DNA methylation takes place at a cytosine base
located at the 5′ to guanosine, in a sequence known as the CpG dinucleotide5. The regions of CpG are shown in cancer and
Figure 2 | Diagram shows the
DNA methylation within cancer and healthy cells (adapted from 13 l The CpG
islands indicated as “c” within the promoter region are actively
transcribed within normal cells and are un-methylated, permitting transcription
activities (indicated by green arrow).
The CpG islands elsewhere in the genes
and the intergenic space are methylated (indicated as “M”). The red arrow
(deleted with an “X”) indicates transcription which is repressed. However,
within cancer cells, the reverse holds true13.
Epigenetics field is thrilling and evolves areas
of investigation within the cancer research and also therapeutics11.
Possibilities of HDAC inhibitors to overcome the resistance of hormonal therapy
in patients with advanced breast cancer is highlighted currently. However, a
confirmatory trial is required before information can be used within clinics11.
We can identify the robust biomarkers by forecasting response to HDAC
inhibitors. However, confirmation is necessary for clinical trials in the