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Impact of MicroRNA Polymorphisms
on Breast Cancer Susceptibility
3
Nusrath Yasmeen, Vikram Kumar, and Krutika Darbar Shaikh
Abstract
MicroRNAs (miRNAs) are considered as the microma nagers of gene expression.
They are said to be involved in several physiological and pathological processes.
They are capable of altering the hallmarks of cancer and hence are considered as
prominent cancer biomarkers. More recently, the microRNAs related polymor-
phism, i.e. single nucleotide polymorphisms (SNPs) or (poly-miRs’) are reported
and are exhaustively being studied. SNPs or (poly-miRs’ ) might occur in the
miRNA biogenesis pathway, in miRNAs themselves or in their target binding
sites, the consequences of such polymorphism, and its impact on life still remain
dubious. miRNAs have known to be implicated in several diseases including
cancer, revealed from a pool of studies performed in past years. Moreover, several
N. Yasmeen (*)
Amity Institute of Biotechnology, Amity University, Jaipur, Rajasthan, India
Faculty of Pharmacology, College of Nursing, King Saud Bin Abdul Aziz University for Health
Sciences, King Abdullah International Medical Research Centre (KAIMRC), National Guard
Health Affairs, Jeddah, Saudi Arabia
King Abdullah International Medical Research Centre (KAIMRC), National Guards Health Affairs,
Jeddah, Saudi Arabia
e-mail: yasmeenn@ksau-hs.edu.sa
V. Kumar
Faculty of Biotechnology, Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur,
India
K. D. Shaikh
King Abdullah International Medical Research Centre (KAIMRC), National Guards Health Affairs,
Jeddah, Saudi Arabia
Faculty of Anatomy, University College of Pre-Professional Studies, King Saud Bin Abdul Aziz
University for Health Sciences, Jeddah, Saudi Arabia
#
The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2021
A. S. Sameer et al. (eds.), Genetic Polymorphism and Cancer Susceptibility,
https://doi.org/10.1007/978-981-33-6699-2_3
53
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studies have reported a strong association between SNPs to susceptibility as well
as the prognosis towards cancer. Polymorphisms in miRNAs are even found to be
associated with breast cancer and evidential support suggests that they substan-
tially incre ase breast cancer susceptibility. In this chapter, we will summarize and
discuss the most recent shreds of evidence explaining the role of miRNAs and the
poly-miRs’ in cancer pathogenesis, with particula r emphasis on breast cancer
susceptibility and prognosis.
Keywords
Breast cancer susceptibility · miRNA · miRNA polymorphism · miRSNPs
Abbreviations
3
0
-UTR 3
0
-untranslated regions
ADRB2 Gene coding for beta-2 adrenergic receptor (β2 adrenoreceptor)
Ago Argonaute
BRCA1 Breast cancer type 1 susceptibility protein
BRCA2 Breast cancer type 2 susceptibility protein
C. elegans Caenorhabditis elegans
CI Confidence interval
CLDN12 Gene coding for Claudin-12
CLL Chronic lymphocytic leukemia
CSCs Cancer stem cells
DFS Disease-free survival
DGCR8 DiGeo rge syndromecriticalregiongene8
DHFR Dihydrofolate reductase
EIF2C1/2 Eukaryotic translation initiation factors 2C 1 and 2
EMT Epithe lial-mesenchymal transition
Expo/Xpo Exportin
GEMIN 3 Gem-associated protein 3
GEMIN 4 Gem-associated protein 4
GWASs Genome-wide association studies
HCV Hepatitis C virus
HIF1AN Gene coding for Hypoxia-inducible factor 1-alpha inhibitor
KRAS-V V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
LNA Locked nucleic acid
miRNA microRNA
miRNPs miRNA-containing ribonucleoprotein particles
MMP Metalloproteinase
OR Odds ratio
OS Overall survival
Pol II Polymerase II
Pol III Polymerase III
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Pre-miRNA Precursor microRNA
Pri-miRNA Primary miRNA transcript
RA Rheumatoid arthritis
RAN RAS-related nuclear protein
RISC RNA-induced silencing complex
RPS6KB1 Ribosomal protein S6 kinase B1
SLE Systemic lupus erythematosus
SNPs Single nucleotide polymorphism
TARBP 2 Transactivation-responsive RNA-binding protein2
TNRC6A Trinucleotide repeat-containing gene 6A
ZNF839 Zinc finger protein 839
3.1 Introduction
Cancer is an umbrella term used for an array of malignant neoplastic diseases. It is
characterized by several hallmarks, e.g. invasion, angiogenesis, and metastasis.
Cancer develops due to modulation in genetic and epigenetic patterns that are
responsible for altering the phenotype of the cells in which they occur (Ahmad
and Shah 2020). Among different cancer types, breast cancer is the second most
prevalent female cancer type and is the predominant carcinoma leading to incre ased
mortality rates among women worldwide. According to the recent statistics, 2 million
new breast cancer cases were diagnosed in 2018 (23% of all cancers) and nearly
6.6% of cancer deaths were reported globally ranks it to be second among women
fatalities (Zaidi and Dib 2018). Several epidemiologic studies revealed that breast
cancer etiology is the most complicated among various cancer types. It varies
according to time of exposure to hormone replacement therapies (HRTs), the
menopausal status of women, age and ethnicity of the patient, genetic predisposition,
and environmental factors. Moreover, differences in the risk and prognosis of the
disease are associated with the given multiple endogenous and exogenous factors
(Shah et al. 2014).
MicroRNAs (miRNAs) are endogenously synthesized, single-stranded, small
non-coding RNA molecules that are 19– 25 nt long (Ragusa et al. 2015). MiRNAs
are evolutionarily conserved non-coding proteins that bind to complementary
sequences in the 3
0
untranslated region (3
0
UTR) of target mRNAs and prevent
their translational inhibition or degradation (Liu and Xu 2011).
3.1.1 Brief Overview of History and Biogenesis
of MicroRNA(miRNA)
In the year 1993, Ambros and Rukvun et al. discovered a small endogenous RNA
lin-4 that is used to regulate developmental timing in nematode Cae norhabditis
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elegans. The regulatory effect of lin-4 was due to the downregulation of the lin-14
transcription factor, this downregulation is essential during the transformation of the
larval stage from L1 to L3 (Bhaskaran and Mohan 2014). Later in 2000, two separate
groups discovered that let-7, a small RNA, was crucial for the transformation of a
larval stage to adult by targeting lin-41 in C. elegans (O’Carroll and Schaefer 2013).
The biogenesis of miRNA is a sequential multi-step process as shown in Fig. 3.1.
miRNA biogenesis begins with the generation of long primary miRNAs (500–3000
nucleotides long) initially transcribed by RNA polymerase II. Primary miRNA has a
5
0
guanosine cap and a 3
0
polyadenylated tail. These can be either coding or
non-coding regions (present in the core of the intron of a coding gene). The primary
miRNAs are then cleaved by Drosha/DGCR8, i.e., a multiprocessor complex to form
precursor miRNAs (pre-miRNAs), that are 60–70 nucleotides long. The Drosha is a
nuclear RNase III enzyme and DGCR8 is DiGeorge syndrome critical region gene
8 (DGCR8) or Pasha constituting compo nents of microprocessor complex. The
hairpin-like structured precursor miRNAs(pre-miRNAs) that are generated are
exported from the nucleus to the cytoplasm, following Drosha processing by
Exportin-5 (EXP 5/XOP5)/Ran-GTP complex. In the cytoplasm, the pre-miRNAs
are finally processed into mature ~18–23-nucleotide-short double-stranded miRNA
duplexes. Dicer, TRBP, or PACT, and Argonaute (Ago1–4) proteins modulate the
Fig. 3.1 Schematic illustration of microRNA biogenesis
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processing of pre-miRNA along with the assembly of the RNA-induced silencing
complex (RISC) (He et al. 2016).
The mature miRNA is subsequently processed by Dicer, an RNase III endonu-
clease, into short double-stranded miRNA duplexes. Two strands of mature RNA are
separated. One strand of the duplex is termed the guide strand (unstable base pairing
at the 5
0
end) along with RNA-binding proteins such as trinucleotide repeat-
containing gene 6A (TNRC6A), links with catalytic Argonaute (AGO) proteins,
forming a micro-ribonuclear protein complex (miRNP) called RISC. RISC includes
GEMIN3 and GEMIN4 that have a significant role in miRNA processing and target
gene silencing. The function of the guide strand is as a mature miRNA, and the other
strand, known as the passenger strand. Ago2 is a very crucial protein as it has slicer
activity. It transits between nucleus and cytoplasm via GW182 family of proteins.
The Ago2 proteins mediate complexation between miRNA and its target mRNA at
3
0
untranslated region in a sequence specific fashion. This complexation further
induces target repression through poly(A)tail shortening of mRNA, also translational
repression and mRNA destabilizatio n. However, scientific data reveals that miRNA
biogenesis can be microprocessor independent through the mirtron pathway. Short
introns with hairpin potential, named “Mirtrons,” can be spliced and debranched into
pre-miRNAs by bypassing Drosha cleavage (Lin and Gregory 2015; Wu et al. 2018).
The biogenesis of miRNA is illustrated herein Fig. 3.1.
3.1.2 Functional Abilities of MicroRNA(miRNA)
miRNAs are non-coding RNA molecules, and their discovery has led to an
improvised understanding of gene expression and regulation. The biological
functions of miRN As in different cellular processes and their abnormal expression
levels in various diseases can be unraveled by highly sophisticated experimental
models such as transgenic overexpression studies and animal knockout models
(Hammond, 2015). The mechanism of action of miRNAs remains elusive and
several theories suggesting their modus operandi have been proposed. The most
widely used theory reports that miRNAs cause mRNA degradation, translational
repression by base pairing with mRNA. The translational repression might be due to
decreased translat ional efficiency or due to aberrant mRNA levels. Subsequently,
insufficient complementarity leads to mRNA degradation and translational inhibi-
tion (Bhaskaran and Mohan 2014). In normal physiological processes, miRNAs are
crucially involved in feedback circuits constituting buffering effects that confer
robustness to miRNA functions.
Several recent experimental studies proved that miRNAs are involved in crucial
biological processes such as apoptosis, cellular proliferation, and differentiation,
along with developmental events like early embryonic stem cell development,
survival, and differentiation, organ development, cellular signaling, and communi-
cation, cell fate determination (Rajman and Schratt 2017). Not only limited to these
actions, but miRNAs are also found to play a role in hematopoietic lineage differen-
tiation, host-viral interactions, and tumorig enesis. Furthermore, miRNAs are
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involved in mature neuronal survival, function, and maintenance. For example,
evidence from several studies confirmed that miR-133b/Pitx3 is responsible for the
maturation and regulation of the midbrain function. Also, it is proved that miR-134
regulates the growth and synaptic plasticity of the nervous system (Huang et al.
2011). Cellular proliferation in glioma cells was inhibited by overexpression of
miR-128 (Zhang et al. 2009). miR-223 was discovered to be responsible for fine-
tuning inflammatory response and of granulocyte production. Suggesting the loss or
deregulation of miRNAs and their genetic ablation could derail the immune system
in mammals leading to pathogenic immune disorders and also cancer (Yuan et al.
2018).
3.1.3 miRNA in Human Cancer
Cancer is a multitudinous disease arising due to derailed genome function. The
sequential carcinogenic events leading to mortality are Initiation, promotion, malig-
nant conversion, progression, and metastasis. Understanding the complexity and
diversity of the functional roles of miRNAs towards development of disease have
paved a way for further investigational studies underpinning the role of individual
miRNAs in cancer. miRNAs are now being considered as prominent diagnostic and
therapeutic tools. Insights into the aberrant miRNAs expression levels in cancer cells
indicate that regulation of miRNAs could be associated with genetic mutations, like
deletion or insertion. Recent years have witnessed an upsurge in the investigational
research finding the association between miRNA and cancer, despite the underlying
complications due to the genetic diversity of cancer cell lines and tumor types and
also the fact that many miRNAs might be deregulated in the same tumor. Moreover,
the functional role of individual miRNA in oncogenesis might be context-dependent
as several transcripts regulate gene expression by miRNA. Different oncogenic
stages mentioned above exhibit different gene expression profiles.
Accordingly, miRNAs are regarded as the regulatory molecules with dual
functions in cancer, they can act either as oncogenes termed “oncomirs” or tumor
suppressors (Jansson and Lund 2012). Oncomirs negatively regulate genes, respon -
sible for cell differentiation and apoptosis, leading to tumor development. For
instance, in breast carcinoma, miR-29a is oncogenic whereas it is a tumor suppressor
in lung cancer. MiRNAs involved in regulating apoptosis are termed as
“apoptomiRs” which can be either pro- or antiapoptotic. miRNAs also might
modulate cellular proliferation, metastasis. It is also studied that miRNAs are
involved in stem cell differentiation; influence cancer stem cells (CSCs) formation
and prominent epithelial-mesenchymal transition (EMT) invasion which is crucial
for the development of drug resistance. Cancer onset and its progression are linked to
aberrant expression of miRNA levels that are associated with the modulation of cell
signaling pathways. MicroRNAs are regarded as powerful gene regulators, as single
miRNA can target up to several hundred mRNAs (Acunzo et al. 2015). The miRNAs
involved in breast oncogenesis are listed in (Table 3.1).
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3.1.4 miRNA and Other Human Diseases
Substantial evidence from the previous studies performed in the past few years
revealed that miRNAs are aberrantly expressed in several pathological conditions
such as obesity, insulin resistance, type 2 diabetes, fatty liver disease, and coronary
artery disease. Recent investigations have found an association between heart
function and microRNA expression levels. Evidence suggests that miR-1,
miR-133, and miR-208 are prominent regulators of myocyte differentiation and
heart development. Data suggest that miR-1 is implicated in the modulation of
Ca
2+
handling proteins and is linked to ventricular arrhythmias. Subsequently, it is
reported that certain microRNAs like miR-24, miR-195, miR- 199a are upregulated
in cardiac hypertrophy and end-stage heart failure (Romaine et al. 2015). miR-142 s,
miR-181, and miR-223, and predominantly expressed in hematopoietic cells
regulating hematopoietic lineage differentiation.
MiRNAs also contribute to the pathogenesis of autoimmune disorders such as
Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), and Sjogren’s
syndrome. It is observed that miRNA-126 are downregulated which causes
decreased production of IFN-α hence implicated in the pathogenesis of SLE.
Upregulated expression of mir-146a and downregulated expression of miR363,
miR-498 was observed in CD4+ T cells of RA patients (Chen et al. 2016a).
miR-192 and miR-377 downregulation leads to extracellular matrix accumulation,
podocyte dysfunction, albuminuria, and EMT in diabetic nephropathy
(Chandrasekaran et al. 2012). miR-29a/b, miR-107, and miR-15a are downregulated
suggesting a possible association between miRNAs and Alzheimer’s disease. Evi-
dence from a recent study suggests the possible role of miR-30d towards insulin
gene transcription and insulin secretion in diabetic patients (Maqbool and Hussain
2014). Several such associations between miRNA levels and various diseases are
unfolding regularly from experimental studies.
Table 3.1 Examples of aberrantly expressed microRNA in breast cancer
Type of
miRNAs
Family of
miRNA
Expression of miRNA in breast
cancer References
Tumor
suppressor
Let-7d Downregulated Thammaiah and Jayaram
(2016)
miR-31 Downregulated Tang et al. (2012)
miR-200c Downregulated Tang et al. (2012)
OncomiRs miR-10b Upregulated Piasecka et al. (2018)
miR-21 Upregulated Han et al. (2012)
miR-221/222 Upregulated Piasecka et al. (2018)
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3.2 Polymorphism in miRNA and Cance r
MicroRNAs (miRNAs) act as microregulators capable of translation of several genes
and gene expression, unlike any other gene their coding sequences are prone to
genetic variations. Several kinds of genetic variations exist of which single nucleo-
tide polymorphisms (SNPs) have evolved as the most prominent resource in explor-
ing and understanding the mechanism of carcinogenesis. Single nucleotide
polymorphism (SNP) is a common variation in the DNA sequenc e that occurs
when nucleotides (A, T, C or G) change in nearly 1% of a certa in population. As
evidenced from a recent study in humans it is reported that >95% of single nucleo-
tide polymorphisms (SNPs) were linked to non-coding sequences as identified by
genome wide association studies (GWASs) (Maurano et al. 2012). miRNAs are
acknowledged for their contribution to the control of numerous metabolic pathways,
such as cellular growth and differentiation. They are also considered crucial for their
roles in cell proliferation, cell differentiation, apoptosis, and metabolism (Chen et al.
2016b) as depicted in Fig. 3.2.
Moreover, after the evidence of the existence of miRNA-related polymorphisms,
they were regarded as a gold mine for numerous studies especially in the field of
molecular epidemiology. Consequently, scientists began to assess the association of
genetic polymorphisms with cancer risk. However, the imperative role on point
mutations in miRNA genes or miRNAs-SNPs in cancer development and progres-
sion was confirmed by Croce’s group who reported for the first time the
downregulation due to frequent deletions of miR-15 and miR-16-1 in human B
cell chronic lymphocytic leukemia (CLL) (Ryan et al. 2010).
Based on their potential role MiRNAs are regarded as double-edged swords, as
they can function both as oncogenes (oncomirs) or as tumor suppressors by virtue of
different molecular mechanisms (Joseph and Nair 2013). Oncogenic miRNAs,
commonly termed oncomirs, are upregulated in cancerous cells and their target
being tumor suppressor genes. Increased expression of oncomirs may lead to
inhibition of the expression of tumor suppressor genes. Some examples of miRNAs
upregulated in breast cancer are miR-10b, miR-18a, miR-21, miR-27a, and
miR-206. In contrast, tumor suppressor miRNAs (such as miR-205, miR-27b,
miR-17-5p) are downregulated in cancer cells than in normal cells and act on
oncogenes increasing the oncogenic effects that promote tumorigenesis (Veeck
and Esteller 2010). Currently, in the field of genetics, phenotypic variations for traits
are considered to be of medical importance. The degree of phenotypic variation and
miRNA expression differs between different cell types, cell task complexity, cell
engagements, and the cell’s exposure to a variety of environmental signals hence can
exert an array of functional effects based on the cellular context (Du et al. 2014).
The last decade had witnessed tremendous progress in the field of miRNAs and
cancer, particularly related to miRNA expression patterns, which are emerging as
favorable diagnostic tools and predictive markers of cancer progression and progno-
sis of patients (Bensen et al. 2018). The discovery of germline variants or polymor-
phism in miRNA that are associated with cancer susceptibility is currently a matter
of intense research. The term miRSNP/miRNA polymorphism was coined and
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Fig. 3.2 Illustration depicting the various causes affecting the miR-polymorphism and the effects exhibited due to these alterations which might impact disease
susceptibility and drug response
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defined as a novel class of SNPs/polymorphisms seen in miRNA primary sequences,
miRNA target sites, or miRNA biogenesis genes that interfere with the function of a
microRNA. Recent evidence suggests that expression of at least 20–30% of human
protein-coding genes is modulated by miRNAs. miR-polymorphisms in the human
genome might responsible for various genetic alterations such as chromosomal
translocations, insertions, and deletions, etc., leading to depletion or gain of a
microRNA site/function. The heterozygous and homozygous form of miRSNPs/
polymorphisms could be present in a population (Mishra et al. 2008). This alteration
is made possible by modifying the complementarity between the miRNA and its
target gene having a profound effect on cancer risk, treatment efficacy, and patient
prognosis (Li et al. 2016).
Single nucleotide polymorphisms in miRNA (miRSNPs) in the miRNA
sequences are a class of functional polymorphisms in the human genome which
are considered to the most prominent. Evidence from literature elucidates that the
predominant role of miRNAs is to regulate protein translation by base pairing with
complementary sequences within the 3
0
untranslated regions (UTR) of target
mRNAs. The role of miRNAs may be modified through variations in their individual
sequence (miR SNPs) or in their target sequences (called “miR-TS-SNPs”). Conse-
quently, altering a single base in a miRNA sequence may affect multiple genes and
their binding specificities, profoundly influencing one or more of the sequential steps
in miRNA biogenesis.
All these changes/polymorphisms are attributed to the mode of action of miRNA
that is highly sequence dependent. Moreover, they could potentially alter the effi-
ciency of miRNA binding to the target sites and also the expression of the miRNA
expression of the corresponding gene and its target along with gene transcription
(Palmero et al. 2011). Not only that, miRSNPs in regulatory regions of coding genes
or at quantitative trait loci or in the miRNA-binding sites of mRNAs can affect the
biogenesis and function of miRNAs. Subsequently, they can also alter the processing
of pri- or pre-miRNA, and influence miRNA–mRNA interactions.
3.2.1 SNPs in miRNA Biogenesis Genes and Breast Cancer
Aberrant expression levels of mature miRNAs’ and their association with the
development of cancer is now being investigated. The critical functions of
DROSHA, DGCR8, Exportin-5, RAS-related nuclear protein (RAN), and DICER
in miRNA biogenesis, makes it is very imperative to assume that genetic
polymorphisms in these genes might influence the processing of miRNAs and,
hence, cancer susceptibility. Undoubtedly, several studies have demonstrated that
polymorphism in miRNA target sites, and genes involved in various steps of the
miRNA processing machinery can affect cell phenotype and disease susceptibility.
DROSHA DROSHA with its essential cofactor DGCR8 forms the microprocessor
complex. This microprocessor protein complex is very crucial to execute the first
step in microRNA processing. Dysregulation of DROSHA and DGCR8 also plays a
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