Seminars in Cancer Biology 51 (2018) 22–35

Contents lists available at ScienceDirect

Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Review

Epigenetics of breast cancer: Biology and clinical implication in the era of T

precision medicine
⁎
Barbara Pasculli, Raffaela Barbano, Paola Parrella
Laboratory of Oncology, IRCCS “Casa Sollievo della Sofferenza”, 71013, San Giovanni Rotondo, FG, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: In the last years, mortality from breast cancer has declined in western countries as a consequence of a more
Breast cancer widespread screening resulting in earlier detection, as well as an improved molecular classification and advances
DNA methylation in adjuvant treatment. Nevertheless, approximately one third of breast cancer patients will develop distant
Histones modifications metastases and eventually die for the disease. There is now a compelling body of evidence suggesting that
ncRNAs
epigenetic modifications comprising DNA methylation and chromatin remodeling play a pivotal role since the
Biomarkers
early stages of breast cancerogenesis. In addition, recently, increasing emphasis is being placed on the property
of ncRNAs to finely control gene expression at multiple levels by interacting with a wide array of molecules such
that they might be designated as epigenetic modifiers. In this review, we summarize the current knowledge
about the involvement of epigenetic modifications in breast cancer, and provide an overview of the significant
association of epigenetic traits with the breast cancer clinicopathological features, emphasizing the potentiality
of epigenetic marks to become biomarkers in the context of precision medicine.

1. Introduction novel and more effective therapeutic strategies.

Breast cancer is the most frequent cancer in women and the second
most common cause of cancer related death. It has been estimated that
approximately 1.5 million women worldwide are diagnosed with breast
cancer each year [1]. Oestrogen receptor (ER) and progesterone re-
ceptor (PgR) statuses have been used since the 1970s to identify a
breast cancer subgroup that is responsive to endocrine therapies re-
presenting the first target therapy implemented into the clinics [2].
More recently, the development of monoclonal antibodies targeting the
HER2neu protein that is amplified in approximately 30% of breast
cancers has significantly improved the outcome in both adjuvant setting
and metastatic disease [3]. Although these improvements together with
screening programs, and better education, have led to a significant
decline in breast cancer mortality in the past 15 years, about 25%–40%
of breast cancer patients develop metastases and eventually die from
the disease [1]. Therefore there is an urgent need to understand the
molecular bases of such a diverse behaviour to identifies the subset of
breast cancer patients at high risk of disease progression and investigate
A major milestone in this path has been the definition of five bio-
logically and clinically relevant intrinsic breast cancer subtypes based
on genome-wide expression and DNA copy number analyses: two oes-
trogen receptor (ER) positive subtypes characterized by a relatively low
(luminal A) and high (luminal B) expression of proliferation-related
genes, a subtype enriched for HER2-amplified tumours (HER2-en-
riched), a subtype characterized by the absence of ER, PgR expression
and HER2 amplification (Basal Like) and a subtype with an expression
profile similar to that of normal breast tissue (normal-like) [4–7]
(Table 1). This has led to the development of risk scores based on gene
expression signatures that are currently entering the clinical practice to
identify low risk breast cancer patients in the attempt to spare un-
necessary adjuvant treatment [8]. Nevertheless, even these classifica-
tion systems do not account for all the reported pathological and clin-
ical heterogeneity of breast cancer.

Abbreviations: BC, breast Cancer; ER, estrogen Receptor; PgR,PR, progesteron receptor; HER-2, human epidermal growth factor receptor 2; TNBC, triple negative breast cancer; ncRNA,
non coding RNA; CpG(s), cytosine-phosphate-guanine dinucleotide(s); 5-me-C, 5-methyl-cytosine; DNMT(s), DNA-methyl transferase(s); DH, ductal hyperplasia; ADH, atypical hyper-
plasia; DCIS, in situ carcinoma; BRCA1, breast cancer 1 gene; PFS, progression-free survival; DSS, disease specific survival; OS, overall survival; DFS, disease-free survival; RFS, relapse-
free survival; DNMTi, DNMT inhibitor; PTM(s), post-translational modification(s); E2, estrogen; lncRNAs, long non coding RNAs; rRNA, ribosomal RNA; tRNA, transfer RNA; snRNA,
small nuclear RNA; snoRNA, small nucleolar RNA; siRNA, small interfering; piRNA, Piwi-associated RNA; miRNA, miR:microRNA; lincRNA, long intergenic non coding cRNA; EMT,
epithelial to mesenchymal transition
⁎
Corresponding author.
E-mail addresses: b.pasculli@operapadrepio.it (B. Pasculli), r.barbano@operapadrepio.it (R. Barbano), pparrella@operapadrepio.it (P. Parrella).

https://doi.org/10.1016/j.semcancer.2018.01.007
Received 28 April 2017; Received in revised form 15 December 2017; Accepted 11 January 2018
Available online 12 January 2018
1044-579X/ © 2018 Elsevier Ltd. All rights reserved.

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B. Pasculli et al. Seminars in Cancer Biology 51 (2018) 22–35

Table 1
Breast Cancer Intrinsic Molecular Subtypes and DNA methylation based classifications (Epitypes).

Intrinsic Subtypes Characteristics Surrogate TCGA[103] Stefansson et al Holm et al

classification* [104] [104]

Luminal A High expression of ER and oestrogen related genes. ER positive Group 1 Cluster 3 ET2
Low level of proliferation related genes. PgR positive Group 2 Cluster 1 ET3
Expression of luminal epithelial cytokeratins CK8 and CK18. HER2 negative Group 3 Cluster 2 ET4
Ki67low ET5
Luminal B HER2 neg Low expression of ER and oestrogen-regulated genes ER positive Group 3 Cluster 1
High expression of proliferation-related genes PgR positive/negative
High expression of growth receptor signaling genes HER2 negative ET2
Expression of luminal epithelial cytokeratins CK8 and CK18 Ki67high ET3
Luminal B HER2 pos High expression of proliferation-related genes ER positive ET4
High expression of growth receptor signaling genes PgR negative/positive ET5
Expression of luminal epithelial cytokeratins CK8 and CK18 HER2 positive
Overexpression/amplification of the HER2 oncogene
HER2 enriched HER2 amplification or high HER2 expression ER negative Group 1 Cluster 1 ET6
High expression of HER2 related genes and/or genes located within the PGR negative Group 2 Cluster 2
HER2 amplicon located in the 17q12 chromosome.
TP53 mutations HER2positive Cluster 3
Basal like ER negative ER negative Group 5 Cluster 2 ET7
PgR negative PgR negative
High expression of basal myoepithelial markers, (i.e. CK5, CK 14, CK 17 HER2 negative
and laminin),
High expression of P-cadherin, fascin, caveolins 1 and 2, alpha-beta
crystallin and epidermal growth factor receptor (EGFR).
TP53 mutation
inactivation of the (Rb) pathway.
Genetic instability

2. Epigenetic alterations in Breast cancer
Epigenetic mechanisms have emerged as fundamental players in
breast cancer development and progression [9]. During the early stages
of carcinogenesis, alterations in chromatin structure through DNA
chemical modification (methyl CpG, 5-hydroxymethylcytosine, 5hmC)
and post-translational modifications of DNA bound proteins including
histones, as result of genetic lesions or environmental hits, affect cel-
lular plasticity and favour the oncogenic reprogramming of tumour
progenitor cells promoting the acquisition of uncontrolled self-renewal
properties. At later stages of cancer growth, additional epigenetic
changes, together with subclonal mutations and signals from the mi-
croenvironment, modulate cancer cell phenotype and affect the meta-
static propensity of the tumour [10–13]. More recently, beyond the
classical epigenetic mechanisms, an increasingly recognized role as
epigenetic modifiers is being given to non-coding RNAs (ncRNAs),
especially to miRNAs and lncRNAs [14]. Indeed, while it has been
shown that, similar to protein-coding genes, ncRNAs are susceptible to
epigenetic regulation at transcriptional level, they regulate in turn gene
expression through acting by both themselves and/or their interactions
with DNA and/or proteins. This enables ncRNAs to influence several
genes at the same time hence it is not surprising that the documented
deregulation of ncRNAs in human cancers affects every step (hallmark)
of cancerogenesis and progression till metastatic spread to distant or-
gans. In light of this, epigenome-wide analyses may offer the opportu-
nity to identify novel, typical traits of cancer for improving cancer
prognostication and individualized treatments.
2.1. DNA methylation
In eukaryotes, DNA methylation occurs mainly at cytosines con-
tained within cytosine-phosphate-guanine (CpG) dinucleotides which
are converted by the addition of a methyl (CH3) group to the 5th carbon
of the pyrimidine ring of cytosine resulting in a formation of 5-methyl-
cytosine (5-me-C) [15]. This enzymatic reaction is catalyzed by a family
of enzymes named DNA-Methyl Transferases (DNMTs), which catalyze
the transfer from the methyl group of the S-adenosyl methionine donor.
There are five known types of DNMT enzymes, but only DNMT1
preserves the hemimethylated DNA generated during DNA replication
and is required for copying the DNA methylation pattern from the
template to the daughter DNA strand. Instead, the DNMT3A and B
enzymes are known as de novo methyltransferases and target un-
methylated DNA [16]. DNA hypermethylation typically occurs at CpG
islands, which represent short interspersed DNA sequences that deviate
significantly from the average genomic pattern by being GC-rich, CpG-
rich, and predominantly not methylated. Approximately 70% of anno-
tated gene promoters are associated with CpG islands whose methyla-
tion status generally correlates with transcriptional activity [17].
In breast cancer, promoter hypermethylation has been reported in
more than 100 genes [18]. Many of those genes play important roles in
cell-cycle regulation (e.g. CCND2, CDKN2A), DNA repair (e.g. BRCA1,
GSTP1) apoptosis (e.g. BCL2, DAPK), tissue invasion and metastasis
(e.g. RASSF1A, RARβ, TWIST, HIN1), regulation of cell transcription
(e.g. HOXA5), cell adhesion (e.g. CDH1), and hormone-mediated cell
signaling (ERα, ERβ and THRβ). In addition, genome wide hypo-
methylation also represents a common feature of breast tumours and
frequently occurs in regions of segmental duplications [19]. Moreover,
a number of studies also identified hypomethylated genes in primary
breast tumours including IL10 [20], MDR1 [21], FEN1 [22], NAT1 [23],
CDH3 [24], urokinase [25], synuclein [26], JAGGED1 and NOTCH1
[27].
A growing number of evidences supports a model where epigenetic
reprogramming of breast cancer initiating cells represent a key step in
breast carcinogenesis and in the subclonal evolution that ultimately
leads to the pathological and clinical heterogeneity of breast tumours
[28] (Fig. 1). Indeed, by using a genome wide promoter microarray,
Helou et al. [13] evaluated the DNA methylation profile of ALDE-
FLUOR-positive breast cancer stem cells (bCSCs) and non-bCSCs. They
found that bCSCs have a distinct DNA methylation landscape with TGFβ
signaling as a key epigenetic regulator of their differentiation. Inter-
estingly, the analysis of peripheral blood lymphocytes isolated from
breast cancer patients and healthy controls by Severi et al. [29] found
that the epigenome-wide DNA methylation profile of CpGs within
functional promoters was associated with an increased breast cancer
risk, whereas DNA methylation of genomic regions outside promoters
was associated with decreased risk, thus suggesting that constitutive

23

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B. Pasculli et al.
epigenetic traits play a role in breast cancer development.
Early studies that used a candidate gene approach already found
precise patterns of methylation during the transition from ductal hy-
perplasia (DH), atypical hyperplasia (ADH) to in situ carcinoma (DCIS)
and invasive carcinoma [30–33]. A study assessing methylation levels
of nine genes on synchronous preinvasive lesions, (ADH and/or DCIS)
invasive ductal breast carcinomas (IDC) and normal breasts demon-
strated differential methylation patterns for APC, CDH1, and CTNNB1
gene promoter regions in pathological samples as compared with
normal tissues [34]. Similarly, the analysis of RARβ2, RASSF1A,
MINT17, and MINT13 throughout the key steps of breast cancer de-
velopment, i.e. transitions from DH to ADH to DCIS, identified the hy-
permethylation of RARβ2 and RASSF1A promoters as an early epige-
netic event in BC, representing a putative predictor of malignant
potential [35]. By using a quantitative PCR method for the assessment
of methylated alleles (AQAMA), van Hoesel et al. [36] made a com-
parative analysis of long interspersed nucleotide element-1 (LINE1)
methylation levels in breast-cancer patients, with available normal
breast tissue, ductal hyperplasia, atypical ductal hyperplasia, ductal
carcinoma in situ (DCIS), and invasive carcinoma. They found that
LINE1 was hypermethylated in the benign lesions but became hypo-
methylated in the DCIS and invasive tumours [36].
More recently, Teschendorff et al. have shed new light into the early
epigenetic events that govern breast cancer development [37]. By using
the Illumina 450k bead chip array, they analysed 42 matched normal-
adjacent and cancer tissues and 50 normal tissues from healthy women,
demonstrating the presence of tens to thousands epigenetic alterations
in normal tissue adjacent to cancer, supporting the existence of an
epigenetic field defect [37]. These field defects were also present in a
cohort of 15 normal adjacent and 40 DCISs, with a substantial DNA
methylation increase in DCISs compared with normal adjacent samples.
The distribution of the recognized methylation patterns was strongly
enriched in binding sites for transcription factors associated with
maintaining chromatin structure, including two Polycomb Repressive
Complex 2 (PRC2) members (EZH2 and SUZ12) as well as RBBP5, CTCF
and RAD21. System-level gene promoter analysis also confirmed that
epigenetic field defects target specific signaling pathways, notably WNT
signaling, a stem-cell differentiation pathway, and FGF signaling [37].
2.2. Histone modifications
Histones are nuclear proteins closely associated with DNA mole-
cules responsible for the structure of chromatin, and play important
roles in the regulation of gene expression. Five types of histones have
been identified: H1 (or H5), H2A, H2B, H3 and H4. H1 and its
24
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Seminars in Cancer Biology 51 (2018) 22–35
Fig. 1. CpG DNA methylation changes contributing
to breast cancerogenesis. The most common type of
breast tumour is the invasive ductal carcinoma (IDC,
or No Special Type, NST, according to WHO 2017).
During progression from no-obliged pre-invasive le-
sions (Atypical Ductal Hyperplasia, ADH), and/or
precursor Ductal Carcinoma in situ (DCIS) to in-
vasive and metastatic disease, the epigenetic repro-
gramming of cancer cells leads to an increase in CpG
island promoter methylation, associated with de-
methylation of gene bodies and repetitive sequences.
homologous protein H5 are involved in higher-order structures of
chromatin. The other four types of histones associate with DNA to form
nucleosomes [38]. A major component of epigenetic regulations is re-
presented by the post-translational modifications (PTMs) of histone
tails. These modifications affect chromatin structure by destabilizing
histone interactions with DNA, altering nucleosome contacts, and
forming binding sites for transcriptional regulators[39]. Overall, 60
distinct modification sites have so far been identified within histones
[40]. Among the common PTMs, acetylation of lysine 9 of histone H3
(H3K9Ac) has been classically associated with open and accessible
chromatin regions [41,42]. By contrast, histone methylation can be
associated with either open or compacted chromatin regions, de-
pending on the specific histone aminoacid that is methylated. For ex-
ample, mono- or trimethylation of lysine 4 on histone H3 (H3K4me1 or
H3K4me3) and trimethylation of histone H3 on lysine 36 (H3K36me3)
are associated with open chromatin [41–43]. Whereas, trimethylation
of lysines 9 and 27 on histone H3 (H3K9me3 and H3K27me3, respec-
tively) is associated with compacted chromatin regions resulting in
repression of target genes [44].
In recent years, the evaluation of genome-wide pattern of histone
modifications has made increasingly clear that different combinations
of histone marks can provide more detailed information about cell
identity and disease state [28,45]. For example, the presence of both
the open chromatin mark H3K4me3 and the compacted chromatin
mark H3K9me3 at a promoter can identify imprinted genes [46]. Thus,
the variety and complexity of histone PTMs have led to the “histone
code hypothesis” which proposes that histone PTMs represent an es-
sential mechanism regulating chromatin-template processes, ultimately
influencing physiological and pathological cellular responses [47].
Changes in histone marks have been associated with malignant
transformation and metastatic behaviour in in vitro studies. For in-
stance, by combining biochemical and epigenomic approaches in a cell-
based model mimicking the transformation from human primary cells
to tumour cells, Zhao et al. found a decrease in histones H3K9me2 and
H3K9me3 during transformation. In addition, they identified KDM3A/
JMJD1A, an H3K9me2 demethylase as responsible for H3K9me2 de-
crease [48]. In another study, Messier et al. [49] used a genome-wide
ChIP-Seq approach to evaluate the relative roles of histone H3 methy-
lation (H3K4me3) and acetylation (H3K4ac) in three breast cancer cell
lines mimicking the normal (MCF-10A), tumorigenic (MCF-7) and pro-
metastatic (MDA-MB-231) phenotypes. In both breast cancer cell lines,
there was an increase in H3K4ac marks as compared to the normal-like
MCF-10A, suggesting that this alteration is required for malignant
transformation. By contrast, the global increase in H3K4me3 at pro-
moters was primarily observed in the triple negative MDA-MB-231 cell
B. Pasculli et al.
line, suggesting that it may be linked to an increased metastatic po-
tential. For all the cell lines, gene promoters are differentially marked,
with the normal-like MCF-10A having fewer marked promoters com-
pared to the cancer cell lines. In addition, MCF-7 showed an increase in
the number of promoters marked by acetylation whereas MDA-MB-231
cells displayed an increase in H3K4 tri-methylation. In MCF-7 cells,
H3K4ac was found to play a role in the regulation of ESR response
pathway, whereas H3K4ac, together with H3K4me3, was associated
with the EMT response pathway in the MDA-MB-231 cell line [49].
Altogether, these data indicate that deregulation of histone PTMs play a
pivotal role in the development and progression of breast cancer and
highlight their possible exploitation as prognostic and predictive bio-
markers as well as therapeutic targets.
Recently, the genome-wide binding patterns of activating histone
H3 lysine 4 trimethylation (H3K4me3) and repressive histone H3 lysine
27 trimethylation (H3K27me3) was compared by ChIP-seq analysis in
Human Mammary Epithelial Cells (HMECs), and three breast cancer
cell lines representing the luminal (ZR-75-1), HER2 amplified (SK-BR-3)
and Triple negative/basal (MDA-MB-436) phenotypes. Although the
genomic distributions and the overall detected peaks of H3K4me3 and
H3K27me3 were comparable, thousands of locus-specific binding
events specific for each of the breast cancer phenotypes were char-
acterized. Some of these peaks were shared among all cell types sug-
gesting a role in normal cell development. Other peaks were shared by
the three cancer cell lines but exclusive to HMEC, suggesting that they
are important in cancer initiation and development. Finally, peaks
unique to different cancer cell lines suggested a specific role in cell fate
commitment during breast cancer initiation and development. In par-
ticular, the number of H3K4me3 peaks between normal and each of the
cancer cell lines were comparable while H3K27me3 peaks varied re-
markably among cell types. By analysing the unique genes marked by
H3K27me3 in each cell line, distinct biological pathways were found to
be repressed. The expression patterns of the genes regulated by these
histone marks in each subtype were validated in three independent
gene expression datasets (GSE60785, GSE45827, and GSE69986) and in
a small cohort of fresh frozen breast cancer primary tumours finding a
correlation between histone mark-based gene classifiers and patients
outcome [50].
While the role of core histones has been widely investigated in
breast cancer, very little is known about the putative role of linker
histone H1 in breast cancerogenesis. In a study evaluating the expres-
sion of 6 out of the 7 H1 somatic variants in BC cell lines, the H1.2
variant was found less abundant than other variants at the transcription
start sites of inactive genes, and promoters enriched in H1.2 tended to
be repressed [51]. In another study [52], the H1 phosphorylation
profiles was evaluated in two breast cancer cell lines (MCF-7 and MDA-
MB-231) and in the non-neoplastic MCF-10A cell line. H1 phosphor-
ylation showed a different pattern in the different cell lines. In parti-
cular, in metastatic MDA-MB-231 cell line, the phosphorylation at
threonine 146 was found on both histones H1.2 and H1.4 [51]. Histone
H1 phosphorylation could increase and decrease in response to estra-
diol in MCF-7 and to a PI3 K inhibitor in MDA-MB-231 cells. When
primary breast tissues were stained for the histone H1 phosphorylation
at threonine 146, variable staining patterns were observed with pT146
labelling correlating with tumour grade [52]. Overall, these data sug-
gest critical roles for specific PTM signatures in directing the organi-
zation of distinct breast cancer epigenomes and regulating oncogenic
signaling pathways resulting in the widespread heterogeneity of breast
tumours.
Three categories of histone modification enzymes are currently re-
cognized. “Writers” such as histone acetyltransferases (HAT) which add
modifications, “Erasers” such as histone deacetlylases (HDAC) which
remove PTMs and “Readers” such as 53BP1 which recognize chromatin
bound PTM marks through specific PTM-specific binding domains
[53,54]. The acetylation of histones by HAT changes their charge from
positive to negative, which reduces their interaction with negatively-
25
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Seminars in Cancer Biology 51 (2018) 22–35
charged DNA. This increases accessibility for the transcriptional ma-
chinery, resulting in transcriptional activation and can be reversed by
deacetylation by HDACs [55]. Thus, the epigenetic changes caused by
imbalances between HATs and HDACs heavily affect global transcrip-
tional profiles and contribute to tumour development and progression.
The eighteen human HDAC enzymes are classified into four groups
based on their homology with yeast HDACs [56,57]. Class I HDACs
comprise HDACs 1, 2, 3 and 8 they are localized in the nucleus and are
the most abundant and ubiquitously-expressed HDACs. Class II HDACs
can be further subdivided in class IIa (HDACs 4, 5, 7, and 9) and Class
IIb (HDACs 6 and 8), based on their sequence homology and domain
organization. These HDACs can shuttle between the nucleus and the
cytoplasm and their expression is tissue-specific [55]. Class III HDACs
are structurally homologous with the yeast Sir2 protein but their role in
tumorigenesis is still debated because some of them have dual roles as
oncoproteins and tumour-suppressors [103,104]. Last, HDAC11 is the
sole member of class IV [58].
Only few studies have evaluated the expression of writers and
readers in breast cancer. The histone acetyltransferase (HAT) hMOF
(human males absent on the first), which acetylates H4K20, was found
to be significantly reduced [58]. Conversely, the Eraser LSD1 (Lysine-
specific histone demethylase 1) was highly expressed in oestrogen re-
ceptor negative breast cancer and was associated with a more ag-
gressive behaviour. Finally, reduced expression of LSD1 resulted in
growth inhibition in vitro [59]. The ectopic expression of H4K20me3-
specific histone methyltransferases SUV420H1 and SUV420H2 in breast
cancer cell lines was able to suppress cell invasiveness. On the contrary,
knockdown of SUV420H2 in the immortalized but not tumorigenic
MCF-10A cell line was able to activate invasion in vitro [60].
More data are instead available about the role of HDACs in breast
tumorigenesis. Indeed, a significant correlation between HDAC1 higher
expression and positive hormone receptor status [61,62] has been
found. In addition, Muller et al. [63] found that HDAC2 and HDAC3
expression was significantly higher in poorly differentiated and hor-
mone receptor negative tumours. For HDAC2, a significant correlation
was also found with HER2 overexpression [63].
2.3. Non coding RNAs
Based on their size, non coding RNAs are conventionally grouped
into two major categories: small ncRNAs (< 200 nt) and long ncRNAs
(lncRNAs, > 200 bp, up to 100 kb). Alternatively, ncRNAs can be
classified according to their function, namely housekeeping molecules
such as ribosomal (rRNA), transfer (tRNA), small nuclear (snRNA) and
small nucleolar (snoRNA) RNAs, that are usually constitutively ex-
pressed, and regulatory molecules such as small interfering (siRNAs),
Piwi-associated (piRNAs) RNAs, microRNAs (miRNA, miRs) [64,65]
and long non coding RNAs (lncRNAs) [66,67].
Considering ncRNAs in the framework of epigenetic regulation of
gene expression comes from the fact that molecular intermediaries of
the epigenetic modifications such as DNMTs, HDACs, and Polycomb
proteins have been demonstrated experimentally to function as targets
of miRNAs or co-factors of lncRNAs [14], thus ncRNAs may be referred
to as epigenetic modifiers. On the other hand, since the mechanisms by
which both molecules exert gene expression regulation do not affect
DNA sequence, the ncRNAs control of gene expression can be con-
sidered an epigenetic phenomenon itself, whose aberrations have se-
vere downstream effects and virtually affect every step of cancerogen-
esis.
In the cancer setting, both miRNAs and lncRNAs behave as onco-
genes or tumour suppressor genes as they can be found upregulated or
downregulated. In this regard, while a global downregulation has been
observed for miRNAs in human tumours compared to healthy tissues
[68], the majority of lncRNAs showed to be upregulated owing to their
low expression under physiological conditions [69]. Noteworthy, it has
been documented that dysregulation of ncRNAs in breast cancer can
B. Pasculli et al. Seminars in Cancer Biology 51 (2018) 22–35

derive from aberrant epigenetic regulation of their gene promoters.
Indeed, the analysis of published sequencing-based methylome data by
Li Y et al. [70] found that aberrant methylation at the promoters of
ncRNAs was more frequent than that at the promoters of protein-coding
genes in the breast cancer setting, with the intergenic ncRNAs being the
majority of the aberrantly methylated ncRNAs. Moreover, they dis-
tinguished five patterns of aberrant ncRNA promoter methylation in the
context of genomic CpG islands (CpGs), in which aberrant methylation
occurred not only on CpGs, but also in regions flanking CpG and in CpG-
lacking promoters. Integration with transcriptional datasets confirmed
the association between ncRNA promoter methylation events and cor-
respondent transcriptional changes which were in turn functionally
responsible for deregulation of key intracellular signaling pathway such
as the MAPK signaling pathway.
miRNAs are short (18–25 nucleotides), highly conserved non-coding
RNAs, that induce translation inhibition or degradation of protein
coding mRNAs via imperfect base-pairing to complementary sites on
target mRNAs (MREs, miRNA Response Elements). Breast cancer is
among the first tumours for which miRNA deregulation was docu-
mented through a comparison of 76 cancerous and 10 normal mam-
mary tissues by microarray analysis [71]. In their work, Iorio et al.
identified a signature of 29 differentially expressed miRNAs able to
predict the nature of the samples (i.e., tumour or normal breast tissue)
[71]. Among them, some (e.g. miR-21 and miR-155) were upregulated
whereas others (e.g. miR-10b and miR-145) were downregulated in BC,
suggesting that each miRNA plays a differential role in the pathology of
breast cancer (few examples are reported in Table 2). Soon after, other
miRNA signatures such as the 46-miRNA signature found by De Ri-
naldis et al. [72], including 13 highly expressed miRNAs in basal-like,
23 highly expressed in luminal tumours (A or B), 6 in normal-like and 4
in HER2 tumours, and others demonstrated the power of miRNAs to
even stratify BC subtypes [73,74].
LncRNAs represent the largest family of non-coding transcripts, in-
cluding long intergenic ncRNAs (lincRNAs), enhancer ncRNAs (eRNAs),
natural antisense transcripts (NATs), and others [66,67], and the me-
chanisms by which they may operate in tumours are emerging as dis-
parate and finely orchestrated [75]. Like protein-coding mRNAs, they
are frequently transcribed by RNA polymerase II and undergo co-
transcriptional and post-transcriptional processing events [76], al-
though they appear not to possess coding potentials. Importantly,
compared to miRNAs whose molecular targeting is based on their pri-
mary sequence specificity for target sites within target mRNAs, lncRNAs
are able to fold into more complex secondary or tertiary structures to
serve their function and to interact with different types of molecules,
i.e. DNA, RNA and proteins, thereby participating to multiple reg-
ulatory networks represented by chromatin remodeling, alternative
splicing, transcriptional and post-transcriptional gene regulation, mo-
lecular decoys for miRNAs [77].
Like miRNAs, lncRNAs have been found to be differentially ex-
pressed between breast cancers and normal mammary tissues sup-
porting their role in cancerogenesis [78] HOTAIR (HOX antisense in-
tergenic RNA) was the first lncRNA observed deregulated in breast
cancer where it showed higher levels in primary tumours compared to
adjacent tissue [79]. Noteworthy, this lncRNA has been recognized as
involved in the transcriptional regulation of HOXD10, the well-known
target of the metastasis-promoting miR-10b, and has also been shown to
promote breast cancer metastasis [80]. Indeed, HOTAIR is involved in
reprogramming the chromatin state, causing increased Polycomb re-
pressive complex-2 occupancy on promoters of genes that inhibit breast
cancer progression, including HOXD10 [79,81]. Similarly, metastasis-
associated lung adenocarcinoma transcript 1 (MALAT1) upregulation
was found in primary BC and its levels were further increased in the
correspondent metastases [58]. The findings from this study suggest
MALAT1 being a co-transcriptional splicing scaffold that cooperates to
the transcription and splicing of pro-tumorigenic genes such as in-
tegrins, ECM proteins, and genes involved in migration and metastasis
throughout the tumour progression. Interestingly, alternative spliced
variants of MALAT1 could be differentially expressed with regard to
full-length transcript and showed independent prognostic performance
for MFS [82], underlying the complexity of the mechanisms by which
lncRNAs regulate changes in the tumour phenotype.
3. Epigenetics traits in the era of precision medicine
According to the National Institutes of Health (NIH), precision
medicine is &ldquo;an emerging approach for disease treatment and
prevention that takes into account individual variability in genes, en-
vironment, and lifestyle for each person&rdquo;. This new concept of
medicine contrasts with the previously &ldquo;one-size-fits-all&rdquo;
approach, in which disease treatment and prevention strategies are
targeted to the average person, without considering individual differ-
ences [83]. As we discussed above, there is now a compelling body of
evidence sustaining the pivotal role of epigenetic mechanisms in the
development and progression of breast cancer. The point is how

Table 2
Deregulated miRNAs and associated cancer hallmarks in breast cancers.

microRNA Expression level Main Targets Downstream effect Cancer Hallmark Refs
in BC

miR-155 Increased SOCS1 Induction of STAT3 mediated inflammatory signalling Tumor-promoting inflammation [183–186]
SOCS1 Induction of HK2 Deregulating cellular energetics
C/EBPβ
RHOA E-cadherin expression inhibition Activating Invasion and metastasis
miR-26b, miR- Decreased CDK8 Evading cell cycle arrest at the G0/G1 phase Sustaining proliferative signaling [187, 188]
107
miR-21 Increased Bcl2 Blockade of apoptosis and activation of cyclin-dependent Evading growth suppressors, Resisting [189–191]
PDCD4 kinase inhibitors (e.g. p21), and deregulation of anchorage- cell death, activating invasion and
TIMP3 independent growth. metastasis
TPM1
SERPINB5
miR-10b Increased HOXD10 Activation of RhoC, urokinase plasminogen activator Activating Invasion and metastasis [192, 193]
KLF4 receptor, α3-integrin, MT1-MMP
Neurofibromin
miR-200 family Decreased ZEB1/ZEB2 Loss of epithelial marker (e.g. E-cadherin) Activating Invasion and metastasis [194–197]
FOG2, Fibronectin,
Moesin, BMI-1
miR-205 Decreased ZEB1/ZEB2 Activation of HER2 mitogenic pathway Activating Invasion and metastasis [198]
HER3
VEGF-A

26

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B. Pasculli et al.
epigenetic traits can be exploited to improve management of breast
cancer patients. Indeed, due to their fundamental biological role, epi-
genetic traits represent suitable biomarkers for early detection, prog-
nosis or therapy response predictors.
3.1. Diagnostic biomarkers
The detection of breast cancer in the early stages of development is
the key for a successful treatment of the disease. Methylated DNA can
be detected at a very high degree of specificity even in the presence of
an excess of unmethylated DNA. Aberrant promoter methylation has
been detected with a high degree of concordance in Fine Needle
Aspirate (FNA) and primary tumours, but not always showed a better
sensitivity and specificity as compared with cytological examination
[84,85]. Atypical and malignant cancer cells can be also found in ductal
lavages or spontaneous produced ductal fluid (Nipple Aspirate). Since
cytomorphological analysis of these specimens is often unsatisfactory,
previous studies evaluated the possibility to detect tumour in ductal
lavages by analysing promoter methylation of several genes. However,
promoter methylation was also detected in healthy individuals and was
unable to distinguish between pre-invasive and invasive lesions
[86,87].
It is now well established that serum and plasma carry significant
amount of cell-free DNA that can be analysed to detect genetic ab-
normalities present in the tumour. Indeed, cell-free DNA from plasma
was used in DNA methylation analysis of APC, GSTP1, RAR-β, and
RASSF1A for early cancer detection [88]. This study showed that the
methylation of the selected genes increased with tumour progression
and that additional breast cancer–specific genes could ameliorate the
sensitivity and specificity of this approach. To date, alongside circu-
lating DNA, the documented stability of ncRNAs, especially miRNAs, in
bodily fluids [89–95] has unveiled the potentials of circulating ncRNAs
to help diagnose breast cancer. For instance, the first report found that
miR-195 and let-7a expression were significantly elevated in BC pa-
tients compared to healthy controls [96], and these levels diminished
after the surgical resection of the tumour mass. High levels of circu-
lating miR-21 and miR-10b were found to be associated with ER ne-
gativity, whereas high miR-155 was associated with PR positivity [97].
Upregulation of miR-155 in BC patients sera was validated by addi-
tional studies [93,98] and, more interestingly, while miR-155 was
likely to distinguish BC patients with both primary and metastatic
disease from controls, miR-10b and miR-34a were significantly differ-
entially expressed only in patients with metastatic disease [93,98]. Of
note, cell-free miR-181a-5p represents one of the most reliable candi-
date biomarker as its decreased levels of expression in the serum of BC
patients compared to healthy controls were confirmed in more than one
study [99]. Circulating miRNA signatures were also proposed as diag-
nostic markers in large cohorts of BC patients [100]. Additional studies
demonstrated that also lncRNAs can be detected in bodily fluids. For
instance, the serum expression levels of circulating lncRNA RP11-
445H22.4 were found significantly increased in BC patients, identifying
BC cases with 92% sensitivity and 74% specificity [94]. Noteworthy,
lncRNA prostate cancer gene 3 (PCA3) has been found to be strongly
associated to prostate cancer, and it is the first lncRNA that has entered
the routine clinical practice to identify prostate cancer risk in urine
samples (Progensa PCA3 urine test), thereby avoiding invasive prostate
biopsies[101]. This provides evidences of ncRNAs potentiality to be-
come of real utility and use in the patient&rsquo;s management and
care.
3.2. Prognostic biomarkers
DNA methylation profiling and core histone modifications have
been evaluated in breast cancer tissues with the aim to better refine the
molecular classification and improve the prognostic and predictive
abilities in the clinical setting. In a pioneering study, Holm et al.
27
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Seminars in Cancer Biology 51 (2018) 22–35
evaluated 1452 CpG sites (corresponding to 803 genes) in 189 paired
primary breast tumours and normal samples. This study found that
basal-like, luminal A and luminal B breast cancer subtypes harbor
specific methylation profiles [102]. In particular, in the basal like/
Triple-negative BC subgroup, the methylation pattern was defined by
the methylation of five genes (CDKN2B, CD44, MGMT, RB and P73) and
hypomethylation of 11 genes (GSTP1, PMS2, MSH2, MLH1, MSH3,
MSH6, DLC1, CACNA1A, CACNA1G, TWIST1 and ID4) [102].
Subsequently, a number of studies have combined DNA methylation
profile with expression analyses to identify molecular signatures that
may better account for the pathological and clinical heterogeneity of
breast cancer.
Initially, the comprehensive molecular analysis of breast cancer
performed by the Tumour Cancer Genome Atlas Network (TCGA)
identified 5 epitypes. Of those, Group 5 showed the lowest level of DNA
methylation and overlapped with the basal-like subtype, whereas
Group 3 showed the highest levels of DNA methylation and was sig-
nificantly enriched for Luminal B subtype [103]. Stefansson et al.
identified three DNA methylation-based subtypes. In particular, cluster
1 was enriched in luminal B tumours (Epi-LumB) and showed CpG is-
land promoter hypermethylation; while cluster 3 was enriched in basal
tumours (Epi-Basal) and characterized by gene body hypermethylation.
By contrast, HER2 and Luminal A breast tumours were more hetero-
geneous, and only a small subset of the Luminal A showed evidence of a
distinctive pattern of DNA methylation changes (Cluster 3) [104]. More
recently, another study from Holm et al. [105] identified 7 breast
cancer subgroups. Epitypes (ET7) was distinctly associated with basal-
like tumours and presence of BRCA1 mutations, two epitypes were
enriched for HER2-amplified tumours (ET6), and one epitype displayed
a methylation profile similar to normal epithelial cells (ET1). Luminal
tumours were stratified into the remaining four epitypes (ET2, ET3,
ET4, ET5). Two dominant patterns of aberrant methylation were
identified. The first, constitutively methylated in both basal-like and
luminal breast cancer was associated to genes with promoters in a
Polycomb-repressed state in normal epithelial cells, and the second
pattern correlated with gene expression levels and was associated with
methylation in luminal tumours and genes with active promoters in
normal epithelial cells [105]. Overall, these studies agree in identifying
specific methylation clusters (epitypes) for basal like and luminal B
breast tumours, whereas HER2 enriched and luminal A breast cancers
do not show specific methylation patterns (Table 1).
A few studies have analysed the methylation profile of specific
breast cancer subtypes. In particular, the methylome analysis in a large
cohort of TNBCs was able to stratify the population into high, medium
and low risk groups and to identify 17 differentially methylated regions
significantly associated with patient&rsquo;s survival in both univari-
able and multivariable analyses [106]. In luminal breast cancers, by
applying a powerful integrative network algorithm to match DNA me-
thylation and RNA-Seq data from the TCGA, Gao et al. identified two
methylation clusters which correlated with the luminal A and luminal B
subtypes. Indeed, luminal A and luminal B tumours shared the same
epigenetically deregulated traits, but luminal B cancers were char-
acterized by a higher level of methylation than normal tissues [107].
The putative use of histone PMTs as classifiers has been evaluated
by Elsheikh et al. [108] using immunohistochemistry (IHC). Histones 3
and 4 PTMs were evaluated on a large series of breast cancer cases
(n = 880). In particular, histone lysine acetylation (H3K9ac, H3K18ac,
H4K12ac, and H4K16ac), lysine methylation (H3K4me2 and
H4K20me3), and arginine methylation (H4R3me2) marks were eval-
uated. High relative levels of global histone acetylation and methyla-
tion were associated almost exclusively with the luminal-like breast
cancer subset. By contrast, moderate to low levels of lysine acetylation
(H3K9ac, H3K18ac, and H4K12ac), lysine (H3K4me2 and H4K20me3),
and arginine methylation (H4R3me2) were associated with Triple ne-
gative/basal-like and HER2 amplified breast cancer subgroups. Indeed,
loss of histone H4 lysine 20 trimethylation (H4K20me3) was associated
B. Pasculli et al.
with luminal subtypes, and was independently associated with worse
disease free survival in multivariable analysis [108].
In the context of prognostic evaluation, also a discrete number of
miRNAs have been associated with prognosis in breast cancer and a few
have been validated in large cohorts of patients [109]. For instance,
along with its diagnostic potential, high miR-21 levels likely associated
with decreased overall survival (OS) and disease-free survival (DFS) in
early-stage breast cancer patients (stage I/II), with miR-21 expression
in this cohort correlating strongly with histological grade[110]. Simi-
larly, miR-10b was found significantly correlated to DFS, distant me-
tastases and worse OS independently from the prognostic factors used
routinely to stratify patients according to their risk to progress [111].
However, as expected, the statistical power of miRNA panels over a
miRNA alone has been demonstrated by the integrated miRNA/gene
signature in a group of 466 patients with breast cancer from The Cancer
Genome Atlas (TCGA) [112]. The final signature, including 30 mRNAs
and 7 miRNAs (miR-93, miR-103, miR-148b, miR-328, miR-484, miR-
874, and miR-1307), proved to significantly predict OS in a multi-
variable model independent of other clinical pathological character-
istics, and showed the highest prognostic value of distant relapse-free
survival in patients with early stage I and II tumours. Furthermore, the
validation of this signature on 8 independent breast cancer cohorts,
comprising a total of 2399 patients, demonstrated its superior perfor-
mance for risk stratification with respect to other RNA predictors, in-
cluding those comprised in the MammaPrint and Oncotype DX panels.
Single miRNAs and other miRNA panels associated with prognosis are
summarized in Table 3.
Among lncRNAs, HOTAIR expression was shown to independently
predict the risk of metastasis in 164 ER positive BC patients [113].
Whereas, alternative spliced variants of MALAT1 were found differen-
tially expressed with regard to full-length transcript and showed in-
dependent prognostic performance for MFS [82]. Other lncRNAs with
prognostic potentials include both individual transcripts, such as SPRY4
intronic transcript 1 (SPRY4-IT1) [114], LINC00472 [115], and
LINC00978 [116], and lncRNAs signatures [78,117]. In particular, Van
Grembergen et al. [118] have performed a genome-wide transcriptional
survey to explore the lncRNA landscape across 835 breast tissue sam-
ples and 172 normal breast tissues and identified 215 aberrantly ex-
pressed lncRNAs in breast tumours as compared to normal samples. In
particular, lncRNA profiling was able to distinguish ER+ from ER−
tumours and allowed stratification into different molecular subtypes,
thus supporting the potential of being prognostic. For instance, the
lncRNA H19, the first identified imprinted long non coding transcript
[119], involved in EMT and regulating different miRNAs [120], was up-
regulated in luminal A breast cancers. In the same report, an overall
downregulation of lncRNAs compared to the other subtypes was ob-
served In the basal-like subtype, with LINC00993 being the most
Table 3
Examples of miRNAs and miRNA panels with potentials of prognostic biomarkers in breast cancers.
microRNAs Patients’ cohort
Single marker
miR-21 84 early BCs (stage I/II) vs 13 controls
miR-10b-5p 101 BCs vs paired normal tissues
miR-155 92 and 231 BCs
miRNA signatures
miR-128a, miR-767-3p, miR -769-3p 207 early BCs
miR-135a
miR-27b, miR-144, miR-210
miR-342, miR-150, miR-30c
Let-7c/miR99a/miR125b cluster 285 ER positive BCs (from TCGA dataset)
miR-493, miR-155 173 TNBC
miR-30e, miR-27a
miR-200c 172 invasive BCs
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Seminars in Cancer Biology 51 (2018) 22–35
downregulated [119]. Furthermore, HOTAIR was the most up-regu-
lated lncRNA of the HER2+ signature.
3.3. Predictive biomarkers
In Early Breast Cancer, breast conserving surgery or mastectomy
followed by radiotherapy represent the standard of care [121–123].
Decision to treat these patients with adjuvant systemic therapy is
guided by clinical and pathological features of the tumour. Without
adjuvant therapy, 12–58% of women will experience disease relapse
within 5 years [124–126], thus the majority of breast cancer patients
(approximately 75–92%) will receive adjuvant therapy [126,127]. En-
docrine therapy is considered for all ER positive breast cancer patients,
as well as anti-HER2neu treatments is the standard of care in HER2
amplified tumours. In locally advanced breast cancer, systemic treat-
ment including hormone therapy and/or anti-HER2 and chemotherapy
are often used prior to surgery to reduce tumour burden. The most
frequently used chemotherapy regimens contain anthracyclines and/or
taxanes [122,123,128]. Large-scale methylation analyses of breast-
cancer tumours have started to investigate the role of global methyla-
tion differences in association with breast-cancer subtypes and clinical
features. These advances in understanding the key molecular mechan-
isms underlying cancer behaviour holds great potential in identifying
individuals who might benefit from improved modalities and treatment
strategies for breast cancer in line with the ambition of precision
medicine.
The standard prognostic and predictive biomarkers that are cur-
rently used in clinical practice are based on the recommendations of
multidisciplinary consensus panels and include the evaluation of ER,
PgR, HER2, and Ki67 immunoreactivity, together with clin-
icopathological variables including tumour size, lymph node status,
grade, [8,121–123,128]. Martens et al. [129] profiled 200 receptor
positive BCs by using the MethyLight assay and identified 10 genes for
which DNA methylation correlated with resistance to endocrine
therapies [129]. In another study, methylation of the Paired-like
homeodomain transcription factor 2 gene (PITX2) has been associated
with poor prognosis in ER positive, lymph node negative patients
treated only with hormone therapy [130,131]. Furthermore, methyla-
tion of the PITX2 gene promoter was also associated with poor patient
outcome in lymph node positive, ER positive, HER-2/neu-negative
breast cancer patients treated with anthracycline-based adjuvant che-
motherapy[132]. The PITX2 gene encodes a member of the RIEG
(Rieger Syndrome)/PITX homeobox family, and acts as a transcription
factor. Although its role in breast cancer is not clear, PITX2 is involved
in basal and hormone-regulated activity of prolactin thus its reduced
expression may influence prolactin levels within breast cancer tissues
and affect cellular sensitivity to anti-estrogen therapies [132,133].
Expression level Clinical Association Refs
Increased according to Grade Decreased OS, DFS [110]
Increased according to Metastasis Decreased OS, DFS [111]
Increased according to grade, TNM, TNBC subtype Decreased OS [199, 200]
Increased in ER positive Decreased OS [201]
Increased in ER positive Increased OS
Increased in ER negative Decreased OS
Increased in ER negative Increased OS
Increased in Luminal A BCs Increased OS [202]
Decreased in Luminal B and a subset of luminal A BCs Decreased OS
Increased in TNBC Increased OS [203]
Decreased in TNBC Decreased OS
Increased in PR- tumors Decreased OS [204]
Decreased in PR+ tumors Decreased OS
28
B. Pasculli et al.
An integrated approach including chromatin immunoprecipitation,
gene expression analysis and whole genome mapping of transcription
factor-binding sites combined with gene expression profiling was im-
plemented to identify genes involved in the proliferative response to
oestrogen (E2). These analyses identified the increased expression of
the E2-inducible histone variant H2A.Z as significantly associated with
lymph node metastasis and worse overall prognosis [134].
The constitutive activation through serine 139 phosphorylation of
histone H2AX (γ-H2AX) has been associated in breast cancer cell lines
with a triple negative/basal like phenotype and/or with the presence of
BRCA1 mutations. The analysis of a breast cancer cohort including
lymph node negative and triple negative cases (n = 122) demonstrated
an association between H2AX immunostaining and worse prognosis in
multivariable analysis [135]. Notably, upon DNA damage, the phos-
phorylation at serine 139 of the histone H2AX is one of the first events
leading to the activation of DNA Double Strands Breaks (DSBs) repair
pathway, thus the constitutive activation of H2AX in Triple negative/
basal like breast cancer is likely to affect sensitivity to conventional
chemo and radiotherapy treatments [135].
While the majority of HER2-amplified breast cancers are success-
fully treated with specific monoclonal antibodies, 30% of patients
eventually become resistant. A high frequency of PGR, HSD17B4, and
CDH13 methylation has been associated with HER-2 positive breast
tumours [136]. Interestingly, Fujii et al. found an association between
hypermethylation of the HSD17B4 gene promoter and complete re-
sponse to anti-HER2 treatment associated with chemotherapy [137].
DNA promoter methylation of the breast cancer 1 (BRCA1) gene has
been associated to chemosensitivity in TNBC. BRCA1 germline muta-
tions account for 10–55% of familial breast cancers and 2% of breast
cancers overall; nevertheless, 13–40% of sporadic breast cancers bear
BRCA1 gene promoter methylation [30, 138–140]. In a subgroup of 167
TNBC patients who received adjuvant chemotherapy, BRCA1 methy-
lation was an independent favorable predictor of 10 years disease
specific survival (DSS) in multivariable analysis. By contrast, in 675
non-triple-negative breast cancer patients who received adjuvant che-
motherapy, BRCA1 methylation was predictor of worse survival in
univariable analysis [140]. Thus, BRCA1 methylation could represent a
useful biomarker of chemotherapy sensitivity in triple negative tu-
mours. Preclinical studies and breast and ovarian cancer clinical trials
have shown the poly(adenosine diphosphate)-ribose polymerase
(PARP) inhibitors efficacy in BRCA1- and BRCA2-mutant patients
[141,142]. Since BRCA1 promoter hypermethylated tumours show the
same molecular phenotype than BRCA mutated cancers (BRCAness)
[143] it has been proposed that BRCA1 hypermethylation might predict
response to PARP inhibitors. In an in vitro study, BRCA1 hypermethy-
lation was able to confer the same degree of sensitivity to the three
PARP inhibitors as the BRCA1 mutation did [144]. However, there are
no clinical data currently supporting the role of promoter methylation
in the response to PARP1 inhibitors in non BRCA1 mutated breast
cancer patients.
Adding a taxane to chemotherapy improves outcome in breast
cancer patients [145,146]. Interestingly, in a cohort of 102 patients we
demonstrated that aberrant promoter methylation of the KEAP1 (Kelch-
like ECH-associated protein 1) gene was associated in both univariable
and multivariable analyses with a better overall survival (OS) in the
patients&rsquo; group receiving sequential therapy with anthracyclines
and cyclophosphamide followed by taxanes, whereas no association
was found in the group receiving anthracyclines and cyclophosphamide
[147].
The putative role of HDAC as prognostic factor in breast cancer is
controversial. Increased expression HDAC1 but not HDAC3 as de-
termined by IHC was able to predict significantly a better disease free
survival in both univariable and multivariable analyses [107], whereas
Muller et al. [63] did not find any association between HDAC1 or
HDAC2 and prognosis. Higher levels of HDAC6 expression in breast
cancer were significantly associated with small tumours, low
29
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Seminars in Cancer Biology 51 (2018) 22–35
histological grade, and hormone receptor positive status. Accordingly,
patients expressing high HDAC6 mRNA and protein levels had a better
disease free survival as compared with those expressing low levels.
However, multivariable analysis failed to show that HDAC6 mRNA and
protein are independent prognostic factors [148].
The association between histone protein expression and resistance
to anthracyclines was investigated by using a panel of cell lines re-
presentative of the major breast cancer subtypes [149]. Upregulation of
histones H2A and H2 B was a common event in all epirubicin resistant
cell lines as compared with their sensitive counterpart. Moreover,
epirubicin resistance could be reversed by histone deacetylase small
molecules. The involvement of histones in anthracycline resistance was
also evaluated in tumour samples from patients enrolled in the BR9601
adjuvant clinical trial by using gene expression analysis. In particular,
patients showing low expression of an 18-genes histone module,
benefited from anthracycline treatment more than those with high ex-
pression [149].
Last, candidate predictive biomarkers have been investigated
among ncRNAs but only a few have shown to associate with treatment
response in large patient cohorts. For example, higher miR-126 was
identified as being associated with increased MFS in a small cohort of
breast cancer patients [150], and more recently was associated with
increased RFS (Relapse Free Survival) in a cohort of tamoxifen treated
BC patients [151], probably due to the coordinated targeting of the pro-
apoptotic genes IGFBP2, PITPNC1 and MERTK [152,153]. Interestingly,
miR-342 and miR-30c were associated with decreased distant relapse in
ER-negative breast cancers [151], while both were found to associate
with clinical benefit in tamoxifen-treated patients [154,155]. Further-
more, miR-301 was shown to mediate resistance to tamoxifen and as-
sociate with increased risk of relapse [156]. In this regard, the precise
mechanisms of regulation of tamoxifen resistance remain largely un-
known but the molecular targeting of PTEN by miR-301 in human
breast cancer suggests the involvement of the miR-301/PTEN/Akt axis
in the development of tamoxifen resistance. As concerns resistance to
other therapies, miR-128 was found associated with sensitivity to
chemotherapeutics via Bmi-1 and ABCC5 regulation [157]; plasma
miR-221 correlated with overall response rate in a cohort of che-
motherapy-treated patients [158], whereas circulating miR-125b pre-
dicted chemotherapy resistance [159]. Yet, high plasma levels of miR-
210 were associated with resistance to anti-HER2 Trastuzumab therapy
[160] whereas high levels of miR-155 sensitized breast cancer to
radiotherapy [161].
Among lncRNAs, BC anti-estrogen resistance 4 (BCAR4) has been
shown to predict tamoxifen resistance [162]. On the other hand,
LINC00160 and LINC01016 were found to be downregulated in ER+
compared to ER- tumours and were early predictors of ET response
[163]. Increased levels of lncRNA-ATB (lncRNA activated by TGF-β)
have been associated with Trastuzumab resistance in breast cancer by a
mechanism of endogenous competition for the binding to miR-200c
that led to up-regulation of ZEB1 and ZNF-217, and induced EMT
[164]. Rather, CCAT2 (colon cancer associated transcript 2) down-
regulation identified a subset of BC patients that might benefit from
cyclophosphamide, methotrexate and fluorouracil (CMF) based ad-
juvant chemotherapy [165]. Finally, Chen et al. [166] demonstrated
that overexpression of lincRNA Regulator of Reprogramming (ROR) is
associated chemotherapy tolerance [166].
To date, to the best of our knowledge, the measurement of miRNAs
and evaluation of their biomarker potentialities have been included in
several on-going clinical trials as primary or secondary endpoints
[167].
4. Epigenetic therapies in breast cancer
The intense interest in epigenetics as therapeutic target stems from
the fact that unlike gene alterations, aberrant hypermethylation as well
as histone PTMs are potentially reversible. Currently, there are two
B. Pasculli et al. Seminars in Cancer Biology 51 (2018) 22–35

Table 4
Phase I/II clinical trials evaluating the efficacy of epigenetic therapies in breast cancer.

Therapeutical scheme N° patientsa Trial Phase Efficacyb Refs

Hydralazine 16 locally advanced or metastatic Phase II CR 31%; PR 50%, ORR 81%. [172]
+Doxorubicin BC)
+Cyclophosphamide
Vorinostat 14 BC Phase II No clinical benefits [173]
Vorinostat 43 Metastases on AI Phase II ORR 19% [174]
+Tamoxifen SD ≥ 24 months 21%
Vorinostat 55 Locally advanced or metastatic Phase I/II pCR Her2-positive patients 55% (95%CI 35–72 %), TNBC patients 28% (95%CI [176]
+Doxorubicin BC 11–52 %); ER-positive, Her2/neu negative 0%)
+Cyclophosphamide
Vorinostat 44 metastatic BC Phase I/II ORR 55% 95%CI: 39%–70% [175]
+Paclitaxel
+Bevacizumab
Entinostat 130 (EE 64; EP 66) Phase II randomized PFS 4.3 months EE versus 2.3 months for the EP (HR 0.73 (95%CI, 0.50–1.07; one- [179]
sided P = 0 .055; two-sided P = 0.11)
+Examestane OS 28.1 months EE versus 19.8 months EP (HR, 0.59; 95%CI, 0.36–0.97; P = 0.036)
Adverse effect 11% in EE vs 2% in EP
Entinostat 40 metastatic BC; 13 TNBC; 27 HT Phase II TNBC no clinical benefit; HT resistant PR 1 out of 27 ORR of 4% (95% CI 0–19). [180]
+5-Azacytidine resistant
Panobinostat 12 post-menopause metastatic BC Phase I PR 2 out of 12 [180]
+Letrozole SD 4 out of 12

a
BC Breast Cancer, AI Aromatase Inhibitors; EE Entinostat + Examestane; EP Eamestane + Placebo; TNBC Triple Negative Breast Cancer; HT, Hormone Therapy.
b
CR complete response; PR Partial Response; ORR Objective Response Rate; SD Stable Disease; CI Confidence Interval; PFS Progression Free Survival; OS Overall Survival.

types of epigenetic drugs approved in the clinics: DNMT inhibitors
(DNMTi) and histone deacetylase small molecules inhibitors (HDACi)
[168,169]. The DNA methylation inhibitors 5-Azacytidine (Azacyti-
dine), 5-aza-2′-deoxycytidine (Decitabine) and hydralazine inhibit
DNMTs by forming a covalent bond with the enzyme after incorpora-
tion into DNA. HDAC inhibitors enhance the acetylation of cellular
proteins by blocking HDAC activity [55]. HDAC inhibition affects tu-
mour growth, and apoptosis of cancer cells, whereas normal tissue is
less affected. HDACi are not only able to decompose and condense the
histone–DNA complex, but also the acetylation status of non-histone
proteins [55].
DNMT inhibitors and HDAC inhibitors have demonstrated anti-
tumor activity in several tumour types and some of them have been
recently approved by drug regulatory agencies for the clinical use in
haematological malignancies [168,169]. In breast cancer, both DNMTi
and HDCAi have demonstrated antitumor activity in preclinal studies
[170,171], however the putative clinical benefits of these molecules are
still under investigation in clinical trials (Table 4).
In a proof of concept study, Arce et al. [171] evaluated 16 locally
advanced or metastatic breast cancer patients treated preoperatory with
hydralazine and magnesium valproate, followed by doxorubicin and
cyclophosphamide. A complete response (CR) was reached in 5 out of
the 16 breast cancer patients (31%) and partial response in 8 out of the
16 patients (PR), thus the objective response rate (ORR) was 81%. A
statistically significant decrease in global 5mC content and HDAC ac-
tivity was demonstrated after treatment as compared to pre-treatment
core biopsies [172].
In phase I/II clinical trials, the pan-HDAC inhibitor Vorinostat failed
to reach response criteria for single-agent activity [173] but showed
clinical benefits in combination with anti-estrogen treatment [174] or
chemotherapeutic agents [175,176]. In the first case, Vorinostat was
administered in association to Tamoxifen in 43 women affected by ER-
positive metastatic breast cancer progressing on aromatase inhibitors.
Confirmed objective responses according to RECIST criteria were de-
monstrated in 8 out of 43 (19%) patients and stable disease for more
than 24 weeks in 9 out of 43 (21%) patients. The objective response rate
(ORR) was 19% and the clinical benefit rate determined as response or
stable disease after 24 weeks was 40% [174]. Yet, Tu et al. [176]
evaluated the association of Vorinostat with doxorubicin and cyclo-
phosphamide in 55 metastatic breast cancer patients. Pathological
complete response occurred in 13 of 24 evaluable patients with Her2-
positive disease, in 4 of 15 patients with triple negative disease and
none of 12 patients with ER-positive, Her2/neu negative disease. The
efficacy of Vorinostat in combination with Paclitaxel and Bevacizumab
was evaluated in 54 metastatic breast cancer patients. In the 44 eva-
luable patients treated at the recommended phase II dose, there were 24
objective responses (55%, 95% CI 39–70%). In an intention-to-treat
analysis including all the 53 treated and eligible patients from the phase
I and II portion of the trial, 26 (49%, 95%C.I. 37%-60%) exhibited an
objective response (2 CR and 24 confirmed PR), and 16 (30%) patients
had stable disease for more than 24 weeks.
In a recent Phase I clinical trial, the pan-HDCA Panobinostat also
showed encouraging results in post-menopause ER positive metastatic
disease when administered in combination with Letrozole [177].
The more promising results in breast cancer have been obtained
with Entinostat, an HDAC inhibitor which potently and selectively in-
hibits class I and IV HDAC enzymes and has been demonstrated to re-
verse EMT phenotype in breast cancer cell lines [178]. An ECOG-ACRIN
Phase III registration study is currently ongoing in advanced breast
cancer (E2112, NCT02115282) to confirm the overall survival ad-
vantage observed in combination with Exemestane in the Phase II set-
ting (ENCORE301 trial), that is a randomized, double-blind, placebo-
controlled study on locally advanced or metastatic BC whose disease
progressed on aromatase inhibitors. In this study, the administration of
Entinostat in combination with Exemestane demonstrated an increase
in median PFS in the group treated with Entinostat and Examestane (EE
4.3 months) as compared with the group treated with Examestane and
placebo (EP 2.3 months) (HR of 0.73 95% CI 0.50-1.07; one-sided
P = 0.055). Indeed, Median Overall Survival (OS) was 28.1 months for
the EE group and 19.8 months for the EP group (HR, 0.59; 95% CI,
0.36–0.97; P = 0.036) [179]. Nevertheless, when the efficacy of com-
bining an epigenetic therapy with Entinostat and the DNA methyl-
transferase inhibitor 5-azacitidine (AZA) was evaluated in a phase II
study in women with advanced hormone-resistant or triple-negative
breast cancer (TNBC) with the intention to re-express ER, no significant
clinical benefits were observed [180].
5. Concluding remarks
In closing, we can state that much is known about the pivotal role
that epigenetic marks and ncRNAs play in human cancers, and beside
an in depth mechanistic investigation of their orchestrated networks

30

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B. Pasculli et al.
underpinning cancer traits, many efforts are being made to demonstrate
the suitability of these factors in the clinical setting of BC and other
tumour types. Due to space restrictions, this review does not deal with
the hot-topic of ncRNAs as novel therapeutics, exhaustively reviewed
by these works very recently [181,182]. A global review of the current
literature about the use of epigenetic traits as biomarkers reveals the
existence of several discrepancies that could be related to different
cohorts’ size, sample preparation, availability of profiling technologies,
data analysis. For instance, detection methods for circulating ncRNAs
are the most eligible for clinical implementation as well as the most
affected by issues concerning pre-analytical procedures such as the
choice of the starting material (serum, plasma, whole blood, that are
not inter-changeable) and processing, methods of quantification, ran-
ging from probe-based or LNA-based quantitative PCR array, micro-
array to Nanostring nCounter technology and RNA seq, and the relative
data normalization.
Despite these pending issues, we might expect that along with the
analysis of cancer-related genes mutations and chromosomal aberra-
tions, the characterization of epigenetic modifications and detection of
ncRNAs will enter the routine clinical investigation very soon, towards
the development of novel screening tools for early cancer detection as
well as diagnostic and prognostic devises, and companion tests for
addressing cancer patients to the most beneficial treatments with the
aim to ameliorate the overall management and monitoring of patients.
Acknowledgments
Work in P. Parrella lab is supported by the Italian Ministry of Health
(MoH) co-funded by the European Regional Development Fund “A way
of making Europe” under the TRANSCAN ERA-NET on Translational
Cancer Research grant no. RRC-2014-2354565 and CANCER13-FP-011;
Italian Ministry of Health (MoH) “Ricerca Corrente 2016” and
“5 × 1000” voluntary contributions”; and “Associazione Italiana
Ricerca sul Cancro” (AIRC) IG-1269/2006 and IG-16647/2015.
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