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6.3.3.2 PIK3CA
PIK3CA belongs to kinases that catalyze the phosphorylation of PIP
2
into PIP
3
.It
takes part in cell division, survival, and growth as well as in breast cancer formation
and progression (Boyault et al. 2012).
PIK3CA gene is present on chromosome 3q26.3. It encodes p110 catalytic
subunit of PI3Ks (phosphatidylinositol-3 kinases). SNPs in PIK3CA contribute to
various tumors including BC (Pang et al. 2014).
One of the common polymorphisms that has been extensively studied in the
PIK3CA is rs17849079. This SNP is a silent polymorphism in which C is substituted
by T, causing change of codon ACC to ACT, with both codons encoding threonine
(Naguib et al. 2011). Various studies have associated PIK3CA rs17849079 SNP
with BC (Karakas et al. 2013; Hanafy et al. 2019).
6.3.3.3 ERa and ERb
Estrogen, a steroid hormone, serves in breast growth and development of hormone
dependent BC (Hammond et al. 2010). It acts through its two receptors: the ERα
composed of 595 amino acids is a product of ESR1 gene and ERβ composed of
530 amino acids is encoded by ESR2 gene.
ESR1 gene spans over 140 kb of genomic DNA, containing eight exons and
located on chromosome 6, whereas ESR2 gene also contains eight exons but is
located on chromosome 14. Polymorphisms in both genes can lead to BC in many
populations globally (Yu et al. 2011; Jahandoost et al. 2017; Lipphardt et al. 2013;
Dehghan et al. 2017; Ghali et al. 2018; Chen et al. 2013).
The most characterized SNPs of ESR1, PvuII (rs2234693) and XbaI (rs9340799),
have been associated with BC in many populations of the world (Araujo et al. 2011;
Fig. 6.2 Schematic representation of PI3K signaling pathway
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Ramalhinho et al. 2013; Madeira et al. 2014; Chattopadhyay et al. 2014; Chauhan
et al. 2019). One meta-analysis concluded that in Caucasi an population, ESR1
rs3798577 SNP increased BC risk but ESR1 rs2228480 SNP decreased BC risk
(Li et al. 2016). Another meta-analysis associated ESR1 PvuII polymorphism with
BC risk in Asians only and not in white populations (Zhang et al. 2015). A meta-
analysis concluded that ESR2 rs4986938 SNP may contribute to BC risk (Yu et al.
2011).
6.3.4 SNPs in Xenobiotic Metabolism Genes
Xenobiotics are foreign substances introduced into the body from the environment
and are subsequently metabolized in the body by a series of enzymatic actions to
facilitate their elimination from the body. A major site for xenobiotic metabolism in
the body is the liver and consequently majority of enzymes are present in the liver
cells. Some endogenous substances such as eicosanoids and steroid hormones are
also modified to facilitate their excretion. As a result of xenobiotic metabolism, the
body’s oxidative status is strongly impacted. Huge amounts of ROS are generated in
cytochrome P450 mediated reactions which is chiefly responsible for toxicity of
many xenobiotics. Xenobiotic metabolism (such as drug metabolism) can be
grouped into phase I and phase II. Phase I enzymes activate inactive carcinogens
which are subsequently detoxified by phase II enzymes. The role of genetic
variations in three of the important genes coding for critical enzymes (CYP1A1,
COMT, and GST) in xenobiotic metabolism has been extensively reported to
modulate the BC risk in various populations of the world.
6.3.4.1 CYP1A1
CYP1A1 is an enzyme of cytochrome P450 superfamily and takes part in drug
metabolism and lipid synthesis. A major phase I enzyme of xenobiotic metabolism,
CYP1A1, also known as AHH (aryl hydrocarbon hydroxylase), upon induction by
polycyclic aromatic hydrocarbons (PAHs), activates certain pro-carcinogens into
active carcinogens; consequently it participates in the development of various
cancers in humans (Badal and Delgoda 2014; Go et al. 2015). For example,
CYP1A1 participates in conversion of benzo[a] pyrene, a weak carcinogenic, into
its epoxide, a more potent carcinogen which induces guanine adducts on DNA,
which can cause carcinogenesis, if not repaired.
The CYP1A1 gene is located at 15q24.1 and has seven exons and six introns.
Several polymorphisms have been reported in CYP1A1 gene out of which CYP1A1
m1 (rs4646903; T3801C) and CYP1A1 m2 (rs1048943; A2455G) have been exten-
sively studied. CYP1A1 m1 is a T to C transition resulting in threonine to cysteine
substitution, while m2 in exon 7 leads to an alanine to glycine substitution. The
result of these amino substitutions is enhanced enzyme activity (Garte et al. 2001;
Schwarz et al. 2001).
Meta-analysis has reported no significant association between CYP1A1 m1 SNP
or CYP1A1 m2 SNP and BC (Hussain et al. 2018; Yao et al. 2010; Qin et al. 2014).
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However, earlier studies have associated CYP1A1 m1 SNP with BC risk in several
populations of the world (Naushad et al. 2011). CYP1A1 m2 SNP is reported to
protect Japanese, UK, and US populations from BC (Basham et al. 2001; Miyoshi
et al. 2002; Boyapati et al. 2005; Parada et al. 2017). This is consistent with Chen
et al. (2007) who reported that East Asian women carrying CYP1A1 m2 alleles have
very low risk of BC.
6.3.4.2 GST
The glutathione S-transferases (GSTs) are part of phase II of xenobiotic metabolism
and act as detoxification enzymes that catalyze the detoxification of phase I enzyme
products (such as carcinogens and drugs) by glutathione conjugation, thereby confer
protection against cytotoxicity and DNA from damage (Zhong et al. 1993; Zhang
et al. 1992; Ryberg et al. 1997). GSTs act by conjugation reactions, making the
products such as carcinogens water-soluble which can then be easily excreted out,
thereby protecting the body from their toxic effects (Nebert and Dalton 2006; Soya
et al. 2007).
GSTM1 is located on chromosome 1 and GSTT1 is present on chromosome 22.
Both are highly polymorphic and associated with various cancers (McIlwain et al.
2006). Due to frequent homozygous deletions, the corresponding enzymes lose their
functional activity including their detoxifying capacity (Mondal et al. 2013).
The polymorphisms of GSTT1 and GSTM1 genes exist as null genotypes, which
is a result of deletion of both alleles at a single locus and are located in coding region.
Various meta-analysis have concluded a significant association of these null
polymorphisms with BC (Qiu et al. 2010a; Song et al. 2016; Hussain et al. 2018).
Fig. 6.3 A xenobiotic metabolic pathway
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This is consistent with earlier reports which associated these polymorphisms with
BC risk in various populations in the world such as Greek, Brazilian, Indian, Iranian,
and Portuguese (Ramalhinho et al. 2011; Kakkoura et al. 2015) (Fig. 6.3).
Phase I enzyme CYP1A1 oxidizes estradiol, while phase II enzymes, COMT and
GST conjug ate the oxidation products with glutathione (GSH), thereby prevent
quinone formation which are mutagenic as they can induce adducts in DNA.
6.3.4.3 COMT
COMT (catechol-O-methyltransferase) enzyme degrades and inactivates
catecholamines (such as neurotransmitters dopamine, epinephrine, and norepineph-
rine), as well as drugs and substances having a catechol structure such as catechol
estrogens (Guldberg and Marsden 1975).
The COMT gene is present on chromosome 22q11, encompassing 28 kb of
genomic DNA, encoding a 271 amino acid protein COMT of 30 kd molecular
weight. One of the widely known polymorphisms reported in this gene is COMT
Val158Met SNP (H108L; rs4680), which causes valine to methionine substitution in
the protein. This substitution decreases COMT enzymatic activity considerably
(Dawling et al. 2001), and due to its low activity, it is referred to as COMT- L in
contrast to high activity COMT-H. It has also been reported that COMT-L gene
carriers are at higher risk for BC (Goodman et al. 2002). COMT Val158Met
polymorphism induces thermolability in COMT protein, thereby hindering its role
in estrogen conversion (Dorszewska et al. 2013).
Meta-analysis reported that COMT H108L SNP (rs4680) increases breast cancer
risk in Indian, Mexican, and Turkish populations (OR ¼ 1.28–1.42, 95%
CI ¼ 1.01–1.97) (Hussain et al. 2018), Asian (Rai et al. 2017), and European
populations (Ding et al. 2010). However, Mao et al. (2010) in their meta-analysis
did not report any significant association between COMT H108L SNP and breast
cancer risk.
6.3.5 SNPs in Cell Cycle Regulatory Genes
A vital physiological process of living organisms is the cell cycle. The process of cell
cycle is tightly regulated and a disruption in its control can lead to cancer (Karrman
et al. 2015). Some vital genes regulating cell cycle and thei r SNPs related to BC are
mentioned below:
6.3.5.1 CCND1
Cyclin D1 (CCND1), a protein of 295 amino acids, governs the G
1
/S checkpoint of
cell cycle. It belongs to cyclin family of proteins, whose members function as
regulators of CDK kinases. It interacts with tumor suppressor protein Rb which
positively regulates CCDN1 gene.
CCND1 gene comprises 13,388 base pairs, 5 exons, and is located on chromo-
some 11q13.3. CCND1 G870A (rs9344) SNP, located in the exon-4/intron boundary
of CCND1 gene, is associ ated wi th many cancers (Sameer et al. 2013; Wasson et al.
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2014). CCND1 protein is found to be overexpressed in more than 50% of BC cases
(Buckley et al. 1993).
Several meta-analysis has reported that CCND1 G870A SNP (rs9344) and BC
risk are strongly associated in Indian (Thakur et al. 2018) and Caucasian (Lu et al.
2009; Cui et al. 2012; Soleimani et al. 2017) populations. Akhter et al. (2019)
reported in their meta-analysis that AA genotype of the CCND1 G870A SNP and
BC risk in Caucasian but not in Asian population are significantly associated.
6.3.5.2 CDKN1B (p27)
CDKN1B, also known as p27, functions to inhibit CDKs, thereby preventing
cellular proliferation (Hunter 1993).
The p27 gene is present on chromosome 12p13. It is a negative regulator of cell
cycle as the encoded p27 protein arrests the cell cycle and, therefore, p27 gene is
postulated as a tumor suppressor gene (Kawamata et al. 1995). Certain
polymorphisms have been identified in p27 gene out of which rs2066827 (V109G)
SNP located in codon 109 and rs34330 (79 C/T) SNP located 5
0
UTR at nucleotide
79 have been highly investigated and associated with numerous cancers, including
breast cancer.
Numerous meta-analysis significantly associated p27 rs34330 SNP with BC risk,
especially in Asians (Xiang et al. 2013; Cheng et al. 2017). However, p27 V109G
SNP has not been found to be associated with BC susceptibility by various meta-
analysis (Wei et al. 2012; Jia et al. 2014).
6.3.5.3 ATM
ATM is a Ser/Thr protein kinase of 3056 ami no acids belonging to PI3/PI4-kinase
family. It senses the double-strand breaks in DNA caused due to a variety of DNA
damaging radiation or chemical agents and signals downstream (Abraham 2004;
Derheimer and Kastan 2010; Shiloh and Ziv 2013). Once activated, ATM initiates
cell cycle checkpoint signaling by phosphorylating multiple substrates including p53
and BRCA1 (Kastan and Lim 2000).
The human ATM gene, located on chromosome 11q, spans over 150 kb of
genomic DNA and comprises 66 exons. Numerous SNPs identified in this gene
have been linked to cancer including BC (Lee et al. 2010).
Several meta-analysis reported that BC shares a strong association with ATM
rs664677 (T/C) SNP and ATM rs189037 (A/G) SNP (Shen et al. 2012; Zhao et al.
2019).
6.3.5.4 Her2
Her2 (human epidermal growth factor receptor 2) is a protein of 1255 amino acids
that acts as a receptor in various signaling pathways that regulate cell proliferation
and survival (Okines et al. 2011).
Her2 gene is present on chromosome 17q12. Her2 Ile655Val SNP which leads to
isoleucine (Ile) to valine substitution altering normal Her2 activity is reported to be
associated with cancer, including BC (Mojtahedi et al. 2013; Tong et al. 2009).
6 Role of Genetic Polymorphisms in Breast Cancer 179
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Krishna et al. (2018) reported in their meta-analysis that Her2 Ile655Val SNP
(rs1136201) is associated with BC risk in many population of the world. Wang et al.
(2013a) and Chen et al. (2014) reported significant association between Her2 valine
allele in Her2 Ile655Val SNP and BC risk in Caucasian population.
6.3.5.5 TGF-b1
Transforming growth factor-β is a cytokine which plays a role in cell growth,
differentiation, and survival and in the development of BC (Derynck et al. 2001;
Benson 2004; Massagué 2008; Thiery et al. 2009). TGF-β occurs in three isoforms
among which TGF-β1 is universally expressed (Zheng 2009).
TGF-β1 gene is present on chromosome 19q13. SNPs reported in this gene
include TGF-β1 T869C, TGF-β1*6A, and T869C present in exon 1 and C509T
(rs1800469) and 800 G/A located in promoter region. These polymorphisms associ-
ate with various cancers including BC (Cebinelli et al. 2016). TGF-β1 T869C SNP
(rs1800470) is a cytosine to thymine substitution, resulting in the substitution of
proline with leucine.
Meta-analysis has reported a significant association of breast cancer with TGF-β1
T29C SNP in Asian (Krishna et al. 2020) and TGF-β1 T869C SNP in Caucasian
populations (Qi et al. 2010).
6.3.5.6 pTEN mTOR
The pTEN/ mTOR signaling pathway is an important cell signaling pathway
involved in cell growth and differentiation. Dysregulation in this pathway can lead
to uncontrolled cell cycle and carcinogenesis (Hanahan and Weinberg 2011; Lien
et al. 2017). Activation of PI3K/Akt/mTOR pathway results in cancer cell resistance
to antitumor therapies (Martini et al. 2014). pTEN dephosphorylates PIP3 resulting
in the formation of PIP2, thereby inhibiting AKT signaling pathway (Chung et al.
2009). mTOR activates factors for protein synthesis, thus has a pro-survival effect on
cells (Zoncu et al. 2011; Fingar et al. 2004; Laplante and Sabatini 2012; Edinger and
Thompson 2002).
PTEN and mTOR are both tumor suppressor genes. PTEN gene is present on
human chromosome 10q23 and mTOR gene is present on chromosome 1p36.2.
SNPs of these genes include mTOR rs2295080 (T > G) in the promoter region,
rs2536 (T > C) in the 3
0
UTR of mTOR, and rs701848 (T > C) in the pTEN 3
0
UTR
region that have been well-studied for their role in carcinogenesis (Zhang et al. 2017;
Song et al. 2017).
PTEN rs701848 (T > C) and rs2735343 (G > C) SNPs are associated signifi-
cantly with BC (Li et al. 2017a, b; Chen et al. 2016; Zining et al. 2016). In a study on
Chinese population, Zhao et al. ( 2016) reported that mTOR rs2295080 SNP
decreased BC risk and that mTOR rs2536 (T > C) SNP and BC are not associated.
Slattery et al. (2012) observed that G allele carriers of mTOR rs1057079 SNP had
higher risk of developing BC.
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6.4 Conclusion
Numerous studies have provided evidence of the association of SNPs with the BC
risk. SNPs can lead to alternative splicing, altered or mutated gene product (protein).
Genome-wide association studies (GWASs) have associated about 170 SNPs with
breast cancer and about 14% of heredity breast cancer are due to single-nucleotide
polymorphisms (SNPs). SNPs can be valuable for accurate diagnosis and prognosis
of BC and help in personalized treatment of BC patients. The factors traditionally
used to identify the risk of breast cancer such as size or grade of tumor did not take
genetic background into account. With the identification of SNPs, it is now known
that breast cancer subtypes differ genetically and hence their etiology can be
different; this knowledge can help in early and better diagnosis of breast cancer as
well as its treatment.
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