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Mining and predicting protein-drug interaction network of breast cancer risk

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DOI: 10.1016/j.genrep.2020.100753

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Contents lists available at ScienceDirect

Gene Reports
journal homepage: www.elsevier.com/locate/genrep

Mining and predicting protein-drug interaction network of breast cancer risk T

genes
Muhammad Nahidul Islama, Shams Shah Shaolina, Bikash Kumar Paula,b,c,
Md. Manowarul Islamd, Touhid Bhuyiana, Kawsar Ahmedb,c,
⁎

a
Department of Software Engineering, Daffodil International University, Sukrabad, Dhanmondi, Dhaka 1207, Bangladesh
b
Department of Information and Communication Technology (ICT), Mawlana Bhashani Science and Technology University (MBSTU), Santosh, Tangail 1902, Bangladesh
c
Group of Bio-photomatiχ, Mawlana Bhashani Science and Technology University (MBSTU), Santosh, Tangail 1902, Bangladesh
d
Department of Computer Scince and Engineering, Jagannath University, Dhaka 1100, Bangladesh

ARTICLE INFO ABSTRACT

Keywords: Background and objective: The increasing number of patients of Breast Cancer (BC) is a matter of concern all
Breast cancer around the world. There isn't any specific reason behind this disease to be occurred in the human body. But there
Atypical hyperplasia are such diseases which are counted as a risk factor of BC. Atypical Hyperplasia (AH) and Lobular Carcinoma in
Lobular carcinoma in SITU SITU (LCIS) are two of them. In this research we have collected the gene list of BC, AH and LCIS from the NCBI
Bioinformatics
gene database and then our target was to find out the common genes among them by implementing an inter-
Data mining methods
secting program.
Drug-protein interaction network
Method: Then we used those intersected data to construct and analyze the Protein-Protein Interaction Network
(PPIN), Protein-drug interaction network and so on. After the end of this we have got the most common fun-
damental genes associated with these diseases, the interrelated interaction networks of this 3 disease that will
help us to better understand the common gene structure of them.
Results: We have got a drug signature suggestion for the hub proteins in the PDI network. From PPIN, 9 most
responsible hub genes are obtained. Finally, following the PDI network, 4 of those hub genes were selected
where several drug molecules from DRUGBANK were suggested for each hub gene.
Conclusions: In future by implementing further studies and analyzing those gene structures, it may be able to
notify us to take precautionary steps to reduce the risk of BC.

1. Introduction
Cancer has existed in the human body for many years but now it is
in a dangerous stage. In the Last 50 years the percentage of affected
people has increased significantly. Among different types of cancer,
Breast Cancer (BC) counted as the second most astronomically immense
cancer next to skin cancer. This is the most chronic cancer for women
which affects 2.1 million women per year and even give rise to a no-
table amount of deaths of women (DeSantis et al., 2014) As stated by
the World Health Organization (WHO) 2012 statement, BC is the most
prominent for the death of women for which percentage of death is
almost 23 of all cancer (Ferlay et al., 2010). About one in eight women,
one in 1000 men can be affected by BC in their lifetime (Ali et al., 2011)
and 1.7 million new patients are being included per year (Ferlay et al.,
2019. In 2018, WHO has estimated that 18.1 million new people were
affected by cancer and 9.6 million deaths happened because of cancer
(Boyle and Levin, 2008). By the year 2030, it could be expected that
26,400 thousand new patients and 17,000 thousand people can be died
per year for cancer (Ali et al., 2011). In different continents, the death
rate and incident rate of BC were gradually in Africa 13.72% and
28.66%, Asia 13.21% and 37.5%, Europe 15.93% and 70.08%, Oceania
18.01% and 57.5% and in America 13.94% and 47.5% (Mariotto et al.,
2017). According to American Cancer Society (ACS) January 1, 2019,
inside of the United States at least 3.8 million patients are living with
BC and at least 150,000 patients had metastatic disease (Dupont and
Page, 1985). The main reason for breast cancer is not identified yet.
After having breast biopsy of anyone if the diseases like Lobular Carci-
noma in Situ (LCIS) and Atypical Hyperplasia (AH) are identified, they

Corresponding author at: Department of Information and Communication Technology, Mawlana Bhashani Science and Technology University, Santosh, Tangail
⁎

1902, Bangladesh.
E-mail addresses: kawsar.ict@mbstu.ac.bd, k.ahmed.bd@ieee.org (K. Ahmed).
URL: http://www.mbstu.ac.bd (K. Ahmed).

https://doi.org/10.1016/j.genrep.2020.100753
Received 15 May 2020; Received in revised form 6 June 2020; Accepted 11 June 2020
Available online 15 June 2020
2452-0144/ © 2020 Elsevier Inc. All rights reserved.
M.N. Islam, et al. Gene Reports 20 (2020) 100753

Fig. 1. The flow chart that contains the summarized view of the working procedures that includes the gene collection, filtering, analyzing topological values and then
generating PPI & PDI network where PPI network is used to create and analyze more networks.

Fig. 2. The graphical interface of the Venn diagram that contains the intersecting genes result of the three diseases where BC have a total of 4220 genes, AH have 136
genes & LCIS have 17 genes and after intersecting they all have a common result of 12 genes which will be used for our analysis.

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M.N. Islam, et al. Gene Reports 20 (2020) 100753

Fig. 3. The PPI network constructed with the common genes of BC and associated diseases that show the complete interactions among the proteins that does have
699 nodes and 930 edges among the nodes.

Table 1 have an increased risk of BC.

Topological values of only the hub genes that are generated after the interac- AH is a condition which can happen before BC that can affect the
tions among the proteins. cells and procurement of unusual cells in the breast. This is not any type
Name Betweenness Closeness Neighborhood Topological of cancer but it can be the pioneer of development of BC in your body.
Centrality Centrality Connectivity coefficient When cells of it keep furcation, it becomes more abnormal and this can
be taken into invasive or noninvasive BC. A family history also has some
PGR 0.022057 0.351751 5.636364 0.06662516
risk factor of BC for women (Hartmann et al., 2015). According to the
TP53 0.653973 0.488231 1.304636 0.03807947
CTNNB1 0.371419 0.425265 2.230769 0.01279386 report of Nashville Breast Cohort 1985, on a research survey within 232
PIK3CA 0.249647 0.376684 1.546218 0.07803121 patients with AH there was 4.4% risk ratio to be affected by BC. Ad-
ERBB2 0.1391 0.401123 4.985507 0.02061348 dition to that, 39 people had a family history of BC with AH and their
ESR2 0.038198 0.348698 4.730769 0.0534188 risk ratio was 8.9%. Besides, 193 patients without family history had
CDH1 0.063081 0.378013 5.909091 0.03121735
EZH2 0.079829 0.3433 1.634146 0.10569106
only a 3.5% risk ratio. So, family history also plays a vital role along
MMP9 0.034258 0.300187 1.4 0.13333333 with AH for women to be affected by BC (Hartmann et al., 2015;
Hartmann et al., 2005). Another report by Mayo Clinic, 2005, 2014, the

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M.N. Islam, et al.
Fig. 4. Figure contains one of the topological properties BC, where the value of BC and number of neighbors has been illustrated according to the PPI network. Here
the value of BC is between 0 and 0.675, number of neighbors is between 0 and 300.
risk ratio was 4.34% among 698 patients with AH by all sides
(Hartmann et al., 2005; Hartmann et al., 2014). When someone is di-
agnosed with it, they have increased the risk of BC in the coming year.
Women who have been diagnosed with it develop BC percentage gra-
dually after 5 years 7%, after 10 years 13% and after 25 years 30%
(Mayo Clinic, 2020). To reduce this risk doctors usually recommend
intensive BC screening and medications.
Besides this, the next term comes LCIS which was first marked in
1941 (Cocquyt and Van Belle, 2005) another type of BC named invasive
lobular carcinoma. It begins in the milk-producing glands of breast and
LCIS doesn't reveal any symptoms in the primary stage. When the in-
fected cells are growing it may thickening part of the breast along side's
new lump in the breast with a change of texture in skin over the breast,
such as dimpling or thickening (Chuba et al., 2005). Research shows
that the least risk of developing IBC (Inflammatory breast cancer) after
LCIS is 7.1% at 10 years (King et al., 2015). By another research of
NSABP B-17 study, women identified with LCIS from 1980 to 2009 and
had been perceived at a specific hospital where the ratio of cancer
expansion was nearly 2% per year and converted in 26% just within
15 years [17]. So, as earlier we mentioned that the AH and LCIS are two
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Gene Reports 20 (2020) 100753
big risk factors for BC, here our goal is to find out the common factors
among these diseases and analyzing in different aspects.
2. Methodology
2.1. Data collection
We collected a single dataset for each disease from the NCBI data-
base (https://www.ncbi.nlm.nih.gov/gene). The keyword ‘Breast
Cancer’, ‘Atypical Hyperplasia’ and ‘Lobular Carcinoma in SITU’ were used
to search the specific dataset (Coordinators, NR, 2017). From the pro-
vided dataset, we strained only the ‘Homo sapiens’ dataset. After col-
lecting of the data from NCBI we developed an intersecting program
through R programming language to fetch only the common data from
those 3 datasets. The intersecting result was visualized with the online
interactivenn tool (Heberle et al., 2015).
2.2. Protein-protein interaction network construction
Following the methodology (Fig. 1) after the data collection we
M.N. Islam, et al.
Fig. 5. This figure of CC illustrates the value of CC and the number of neighbors for each CC according to the PPI network. Where the value of CC is between 0.025
and 0.500 and the number of neighbors is between 1 and 400.
started the analyze part. The Generic PPI Network was generated by the
implementation of the common genes in an online tool named net-
workAnalyst (Xia et al., 2015). The STRING interactome database with
900 confidence score cutoff was used here. This database (http://string-
db.org) aims to provide a critical evaluation and integration of PPI,
which includes direct (physical) and indirect (functional) evaluations
(Szklarczyk et al., 2015). Then the PPI network was used in an open
source network analyzing tool named Cytoscape (Shannon et al., 2003)
for the finding and analyzing of the clusters and topological properties.
2.3. Protein-drug interaction network construction
Another feature from the same PPIN generating networkAnalyst tool
(Xia et al., 2015) was used to construct the PDI network. By uploading
the common genes from the intersecting result we generated a PDI
network model. Where, the drug molecules were suggested from
DrugBank database (Version 5.0) for any specific protein, which is
applicable for human data only (Xia et al., 2015) (Wishart et al., 2006).
The online tool (networkanalyst.ca) selects hub proteins automatically.
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Gene Reports 20 (2020) 100753
2.4. Genemania network construction
Genemania is an online tool that works with gene network (Warde-
Farley et al., 2010). We have got some hub genes from the PPI network
and then we used those hub genes to create a network model among
them with this tool. This tool generates hypotheses about gene function
with the capability of analyzing gene list and prioritizing genes for
functional assays (Zuberi et al., 2013). If the functions given here are
poorly characterized then recognizing interacting genes of familiar
function helps predict the function of the unfamiliar gene (Myers et al.,
2005). After giving a gene list into this tool it will represent physical,
predicted, co-expression and some other properties interactions after
searching diverse network data types (Zuberi et al., 2013). After giving
a list of gene as query it will find more genes like this that's the reason it
is also countered as a ‘gene recommender system’ (Mostafavi and
Morris, 2012).
M.N. Islam, et al.
Fig. 6. Figure contains a topological properties TC, where the value of TC and number of neighbors has been illustrated according to the PPI network. Here the value
of TC is between 0 and 0.675, number of neighbors is between 1 and 400.
3. Analysis and results
3.1. Data processing result
After applying some filtering procedures we get 4220 genes for
Human breast cancer, 136 genes for AH and 17 genes for LCIS. Every
single gene has its own unique gene ID and through that gene ID we
merged our collected genes from 3 specific diseases. The merging
process is done by R Programming Language as because it is one of the
most popular Programming Languages for working with data sets and
alongside that we also used two online data intersecting tool for cross
checking purpose. Fig. 2 exhibits the graphical view of Venn diagram of
collected genes for specified diseases which is generated by an inter-
acting Venn diagram tool (Heberle et al., 2015). From the figure, it is
nicely displayed that there are 12 common genes (ERBB2, PGR, EZH2,
PIK3CA, CTNNB1, ESR1, TP53, ESR2, CLDN4, MUC1, CDH1, MMP9) of
selected diseases.
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Gene Reports 20 (2020) 100753
3.2. Generic protein-protein interaction network (PPI network)
Physical proximity of high specificity established between two or
more protein molecules is called PPI (European Bioinformatics
Institute, 2020). Numerous new insights into protein function are given
by the PPI network (Ahmed et al., 2020). The mathematical depiction
of the physical contacts among proteins in the cell with a mesmerizing
graphical view is known as PPI networks (PPIN) (European
Bioinformatics Institute, 2020). The characteristics of those contacts are
to become specific, occurring between described binding province in
the proteins and containing a specific biological denotation (www.ebi.
ac.uEuropean Bioinformatics Institute, 2020). After uploading the in-
tersecting result (ERBB2, PGR, EZH2, PIK3CA, CTNNB1, ESR1, TP53,
ESR2, CLDN4, MUC1, CDH1, MMP9) on an online PPI network ana-
lyzing tool, we found a sub network that is made up within the String
interactome database. Where, we get a PPI Network model with a total
644 nodes including 9 hub genes (CDH1, PIK3CA, TP53, ERBB2, EZH2,
PGR, ESR2, CTNNB1, and MMP9). Fig. 3 shows the network of the
common fundamental genes of the associated diseases. This network
model generated through an online tool that is designed for the
M.N. Islam, et al. Gene Reports 20 (2020) 100753

Fig. 7. The correlations of the average neighborhood connectivity and the number of neighbors is illustrated in this figure following the PPI network where the value
of average neighborhood connectivity is between 0 and 210 and number of neighbors is between 1 and 400.

researcher to analyze gene expression (Xia et al., 2015). Here, every
hub gene has a blue border around them and four of them most sig-
nificant (TP53, CTNNB1, PIK3CA, ERBB2) as these hub genes are vastly
connected with other nodes through edges. The rest of the smallest
sized nodes with pink color have two or more edges connected to them
and the smallest sized purple colored nodes have only one edge con-
nected.
3.3. Topological properties
For better understanding of the interactions between the proteins
we have done some sort of topological analysis through Cytoscape tool
for bio molecular interactions (Shannon et al., 2003). This analysis
includes visualization of some topological properties and also the to-
pological values of top 9 most significant hub genes. These topological
properties were enumerated to define the characterization of proteins
in the PPI network (Yang et al., 2014). Details are shown in Table 1.
3.3.1. Betweenness centrality (BC)
In Fig. 4, BC of a node means its shortest paths between other nodes
in the network. Compute the BC for node S, take a pair of nodes and
find all the shortest paths between them (Özgür et al., 2008). Then find
out the number of nodes that pass through node S and divide it by the
number of shortest paths between the pair of nodes. Central node is like
a bridge in the network that connects the pairs of nodes.
3.3.2. Closeness centrality (CC)
In a network the CC (Fig. 5) of a node means how close it is to the
other nodes (Özgür et al., 2008). When the total distance between the
nodes is smaller than the closeness is higher. CC of a node is the mutual
average shortest path length (Navlakha et al., 2014). In the network, CC
of a node is measured by overturning the distance of sum from it to the
other nodes. Each node Cc is between 0 and 1(Doncheva et al., 2012). It
measures how rapidly the information in the network expands from a
node to other reachable nodes (Doncheva et al., 2012).
3.3.3. Topological coefficient (TC)
TC (Fig. 6) is considered as Tn of a node (n) with the number of
neighbors kn. It is computed as (Doncheva et al., 2012),

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M.N. Islam, et al. Gene Reports 20 (2020) 100753

Fig. 8. The number of nodes for each degree has been illustrated in this topological property following the PPI network. Where the maximum number of node is 600
and the maximum value of degree is 400.

Table 2 3.3.4. Neighborhood connectivity distribution (NCD)

The hub genes and their degrees has been described here where the degree of a NCD (Fig. 7) is the average connectivity of all neighbors of Node n
node explains the number of edges connected to that node. (Doncheva et al., 2012). NCD gives the average of all nodes n with
Name Degree Name Degree neighbors k where k = 0,1, … n (Doncheva et al., 2012). There are
three NCD: only in, only out and in and out (Doncheva et al., 2012). If it
PGR 22 ESR2 26 is a decreasing function in k, there are low and highly connected nodes
TP53 302 CDH1 44
and the edges between them prevail in the network (Doncheva et al.,
CTNNB1 169 EZH2 41
PIK3CA 119 MMP9 15 2012).
ERBB2 69

3.3.5. Node degree distribution (NDD)

Tn = avg. (J(n, m))/kn
J(n,m) defines that all the node m share a minimum one neighbor
with n. J(n,m) is the shared neighbors number between node n and m,
plus 1 if there is an edge between the nodes. Tc is a correlative measure
which a node shares neighbors with other nodes.
The node's degree is the number of total neighbors that remain in
the entire network (Navlakha et al., 2014). It can also be targeted as the
number of edges connected to it where a self-loop edge is defined as two
degrees for that node (Doncheva et al., 2012). Here, the node degree
distribution (Fig. 8) will count the total amount of nodes with degree.
Details are shown in Table 2.

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M.N. Islam, et al. Gene Reports 20 (2020) 100753

Fig. 9. The predicted, co-expression and physical interaction network model that is constructed by the hub genes collected from the PPI network.

for the model organisms. Sometimes the genes with similar patterns of
Table 3
expression have similar functions. And there are some functions which
The network groups and their values in percentage have been described here.
intend to be shared between the genes whose gene products interact
Network Group Network Group Ratio physically. The predictions were made here in GeneMania tool by
merging multiple diverse sources of genomic and proteomic data.
Predicted I2D-IntAct-Mouse2Human 15.70% 34.11%
I2D-INNATEDB-Mouse2Human 9.81% From the PPI Network we got 9 hub genes (CDH1, PIK3CA, TP53,
I2D-BIND-Mouse2Human 8.60% ERBB2, EZH2, PGR, ESR2, CTNNB1, MMP9) those are mostly re-
Co-Expression Boldrick-Relman-2002 8.07% 27.58% sponsible for the network model showed in Fig. 9. So, we will use these
Rosenwald-Staudt-2001 6.97%
proteins to create another model with the online tool GeneMania
Dobbin-Giordano-2005 5.15%
Burington-Shaughnessy-2008 3.27% (Warde-Farley et al., 2010). We will find out some network groups and
Chen-Brown-2002 2.76% their other properties (Predicted, Co-expression, physical interactions
Alizadeh-Staudt-2000 1.37% and others).
Physical Interactions IREF-MPPI 20.20% 23.57% The top 3 network group's connections are shown in the Fig. 9 and
IREF-PUBMED 2.57%
network model values are given in the Table 3. In this table, every
IREF-DIP 0.80%
Others Others 14.74% network group is constructed with some networks. Those networks are
indicating the databases and the percentage of the data fetched from
that following database to create the network in Fig. 9.
3.4. Predicted, co-expression and physical interaction network among the
hub genes 3.5. Clustering

An opportunity is created for the silico prediction of gene function The unsupervised categorization of such patterns like observations,
by using the functional properties of known genes which are generated data items, or feature vectors into groups is known as clustering (Jain

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M.N. Islam, et al.
Fig. 10. The visualized Cluster result using MCODE clustering algorithm.
et al., 1999).
There are several clustering algorithms available like MCL (Markov
Cluster), RNSC (Restricted Neighborhood Search Clustering), SPC
(Super Paramagnetic Clustering), MCode (Molecular Complex
Detection) etc. Here, we have done the clustering of MCode in Fig. 10
and MCL in Fig. 11. MCL is astoundingly vigorous with graph mod-
ification and MCode detects heavily connected areas (Brohee and Van
Helden, 2006).
3.6. Protein-drug interaction network (PDIN)
Working with the protein drug interaction has a crucial importance
to understand the fundamental characteristics of molecule affinity and
a way of resolving this is to interact with drugs for specific protein
targets (Hasan et al., 2020). For the developments of the drugs the
constitutional target of the particular proteins is a major consideration
(Eyers et al., 2018). The study of PDI has a focal importance to un-
derstand the constructional characteristics which are necessary for li-
gand affinity (de Azevedo et al., 2009). Following this reason, we have
constructed the PDI network which is shown in Fig. 12 including the
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Gene Reports 20 (2020) 100753
intersected genes from BC, AH and LCIS. This process produced 4
subnetworks of PDI where 4 major genes (ESR2, PGR, MMP9, PIK3CA)
were being interacted with the drug samples fetched from the DRUG-
BANK database using an online tool (Xia et al., 2015).
4. Discussion
In this study, the PPI network, PDI network, Clusters and topolo-
gical properties including BC, CC, TC, NCD and NDD have been ana-
lyzed that was structured with the common genomic data identified and
collected from BC and it's two associated diseases AH and LCIS.
The process starts by collecting the genes of 3 diseases and use those
3 dataset for intersecting and collecting the common genes. Here we get
12 common genes and use those gene for creating a PPI network. The
same method also works for illustrating the PDI network where the 4
most significant hub genes were selected and some drug molecules was
proposed for those genes.
From the PPI network we identify 9 hub genes (CDH1, PIK3CA,
TP53, ERBB2, EZH2, PGR, ESR2, CTNNB1, and MMP9). The topological
property was also collected following the PPI network using Cytoscape
M.N. Islam, et al.
Fig. 11. Cluster result using MCL clustering algorithm where we got 1 significant cluster network and 2 discrete networks.
tool. And then two different clusters were constructed by the same tool.
After collecting the hub genes, we used those data to create another
network model that shows up the predicted, co-expression and physical
interaction connections. The detailed values of these connections have
also been collected in visualized and table format for further analysis in
future.
We did some background study from some of the previous papers
where other researchers researched with BC, AH & LCIS. Following the
background study we found that in 2007 a paper was published where
the authors described about MRI screening result of 378 patients and
showed the increased risk of BC among the AH and LCIS patients (Port
et al., 2007). In another paper from 2003, we found out that the authors
researched about the diagnosis and management of a term lobular
neoplasia that refers to spectrum of lesions which features AH and LCIS
(Simpson et al., 2003).
By studying such kind of papers from different journals, we noticed
most of them talked about AH & LCIS as two biomarkers of BC. We are
also working here believing this prediction but our main motive is to
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Gene Reports 20 (2020) 100753
work with the PPI network, analyzing several biological network
models and topological properties. So following this work it might be
one more step ahead towards this field.
5. Conclusion
Our study has summarized the relations of BC and its two significant
risk factors. The statistics clearly notify that the AH and LCIS patients
have the risk to carry BC more than others. So we have encountered the
12 common interrelated genes of these diseases. Then the common 12
genes were used for generating the PPI & PDI network and we separated
9 most significant hub genes from the PPI network. 4 of those hub genes
were automatically selected by the PDI network, where several drug
molecules from DRUGBANK were suggested for each hub gene. We also
generated clustering network following 2 mostly used clustering algo-
rithm MCL and MCODE clustering in Cytoscape tool. These tasks de-
serve more background and experimental studies to produce more re-
liable information for future analysis. After doing so, we might be able
M.N. Islam, et al. Gene Reports 20 (2020) 100753

Fig. 12. The 4 sub networks of the PDIN where 4 hub genes has been isolated and their preferred drug molecules from DRUGBANK is suggested.

to mitigate the risk of AH and LCIS patients from being affected by BC CC closeness centrality
in the upcoming future days. TC topological coefficient
NCD neighborhood connectivity distribution
Abbreviations NDD node degree distribution
PI physical interaction
BC breast cancer
AH atypical hyperplasia
LCIS lobular carcinoma in SITU Authors' contributions
PPI protein-protein interaction
PPIN protein-protein interaction network MNI, SSS and BKP carried out the experimental work and provided
PDI protein drug interaction the first draft of the manuscript. BKP, KA, TB and MI supervised the
PDIN protein drug interaction network experimental work and provided manuscript writing assistance. BKP
HG hub gene and KA designed and supervised the work. All authors have read and
BC betweenness centrality approved the final manuscript.

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M.N. Islam, et al. Gene Reports 20 (2020) 100753

Declaration of competing interest Hasan, M.R., Paul, B.K., Ahmed, K., Mahmud, S., Dutta, M., Hosen, M.S., Hassan, M.M.,
Bhuyian, T., 2020. Computational analysis of network model based relationship of
mental disorder with depression. Biointerface Research in Applied Chemistry 10 (5),
The authors declare that they have no competing interests. 6293–6305.
Heberle, H., Meirelles, G.V., da Silva, F.R., Telles, G.P., Minghim, R., 2015. InteractiVenn:
a web-based tool for the analysis of sets through Venn diagrams. BMC bioinformatics
References 16 (1), 169.
Jain, A.K., Murty, M.N., Flynn, P.J., 1999. Data clustering: a review. ACM computing
surveys (CSUR) 31 (3), 264–323.
Ahmed, M.L., Islam, M.R., Paul, B.K., Ahmed, K., Bhuyian, T., 2020. Computational
King, T.A., Pilewskie, M., Muhsen, S., Patil, S., Mautner, S.K., Park, A., Oskar, S., Guerini-
modeling and analysis of gene regulatory interaction network for metabolic disorder:
Rocco, E., Boafo, C., Gooch, J.C., De Brot, M., 2015. Lobular carcinoma in situ: a 29-
a bioinformatics approach. Biointerface Research in Applied Chemistry 10 (4),
year longitudinal experience evaluating clinicopathologic features and breast cancer
5910–5917.
risk. J. Clin. Oncol. 33 (33), 3945.
Ali, I., Wani, W.A., Saleem, K., 2011. Cancer scenario in India with future perspectives.
Mariotto, A.B., Etzioni, R., Hurlbert, M., Penberthy, L., Mayer, M., 2017. Estimation of the
Cancer Ther 8, 56–70.
number of women living with metastatic breast cancer in the United States. Cancer
Boyle, P., Levin, B. (Eds.), 2008. World Cancer Report. 150 cours Albert Thomas, 69372
Epidemiol. Biomark. Prev. 26, 809–815.
Lyon Cedex 08, France. World Health Organization, International Agency for
Mayo Clinic, 2020. last access: 06-06-. https://www.mayoclinic.org/diseases-conditions/
Research on Cancer, International Agency for Research on Cancer.
invasive-lobular-carcinoma/symptoms-causes/syc-20373973.
Brohee, S., Van Helden, J., 2006. Evaluation of clustering algorithms for protein-protein
Mostafavi, S., Morris, Q., 2012. Combining many interaction networks to predict gene
interaction networks. BMC bioinformatics 7 (1), 488.
function and analyze gene lists. Proteomics 12 (10), 1687–1696.
Chuba, P.J., Hamre, M.R., Yap, J., Severson, R.K., Lucas, D., Shamsa, F., Aref, A., 2005.
Myers, C.L., Robson, D., Wible, A., Hibbs, M.A., Chiriac, C., Theesfeld, C.L., Dolinski, K.,
Bilateral risk for subsequent breast cancer after lobular carcinoma-in-situ: analysis of
Troyanskaya, O.G., 2005. Discovery of biological networks from diverse functional
surveillance, epidemiology, and end results data. J. Clin. Oncol. 23 (24), 5534–5541.
genomic data. Genome Biol. 6 (13), R114.
Cocquyt, V., Van Belle, S., 2005. Lobular carcinoma in situ and invasive lobular cancer of
Navlakha, S., He, X., Faloutsos, C., Bar-Joseph, Z., 2014. Topological properties of robust
the breast. Curr. Opin. Obstet. Gynecol. 17 (1), 55–60.
biological and computational networks. J. R. Soc. Interface 11 (96), 20140283.
Coordinators, NR, 2017. Database resources of the national center for biotechnology in-
Özgür, A., Vu, T., Erkan, G., Radev, D.R., 2008. Identifying gene-disease associations
formation. Nucleic Acids Res. 45 (Database issue), D12.
using centrality on a literature mined gene-interaction network. Bioinformatics 24
de Azevedo, J., Walter, F., Caceres, R.A., Pauli, I., Timmers, L.F.S., Barcellos, G.B., Rocha,
(13), i277–i285.
K.B., Soares, M.B., 2009. Protein-drug interaction studies for development of drugs
Port, E.R., Park, A., Borgen, P.I., Morris, E., Montgomery, L.L., 2007. Results of MRI
against Plasmodium falciparum. Curr. Drug Targets 10 (3), 271–278.
screening for breast cancer in high-risk patients with LCIS and atypical hyperplasia.
DeSantis, C., Ma, J., Bryan, L., Jemal, A., 2014. Breast cancer statistics, 2013. CA Cancer
Ann. Surg. Oncol. 14 (3), 1051–1057.
J. Clin. 64 (1), 52–62.
Shannon, P., Markiel, A., Ozier, O., Baliga, N.S., Wang, J.T., Ramage, D., Amin, N.,
Doncheva, N.T., Assenov, Y., Domingues, F.S., Albrecht, M., 2012. Topological analysis
Schwikowski, B., Ideker, T., 2003. Cytoscape: a software environment for integrated
and interactive visualization of biological networks and protein structures. Nat.
models of biomolecular interaction networks. Genome Res. 13 (11), 2498–2504.
Protoc. 7 (4), 670.
Simpson, P.T., Gale, T., Fulford, L.G., Reis-Filho, J.S., Lakhani, S.R., 2003. The diagnosis
Dupont, W.D., Page, D.L., 1985. Risk factors for breast cancer in women with proliferative
and management of pre-invasive breast disease: pathology of atypical lobular hy-
breast disease. N. Engl. J. Med. 312 (3), 146–151.
perplasia and lobular carcinoma in situ. Breast Cancer Res. 5 (5), 258.
European Bioinformatics Institute, 2020 https://www.ebi.ac.uk/training/online/course/
Szklarczyk, D., Franceschini, A., Wyder, S., Forslund, K., Heller, D., Huerta-Cepas, J.,
network-analysis-protein-interaction-data-introduction/protein-protein-interaction-
Simonovic, M., Roth, A., Santos, A., Tsafou, K.P., Kuhn, M., 2015. STRING v10:
networks. (last access: 06-06-2020).
protein–protein interaction networks, integrated over the tree of life. Nucleic Acids
Eyers, C.E., Vonderach, M., Ferries, S., Jeacock, K., Eyers, P.A., 2018. Understanding
Res. 43 (D1), D447–D452.
protein–drug interactions using ion mobility–mass spectrometry. Curr. Opin. Chem.
Warde-Farley, D., Donaldson, S.L., Comes, O., Zuberi, K., Badrawi, R., Chao, P., Franz, M.,
Biol. 42, 167–176.
Grouios, C., Kazi, F., Lopes, C.T., Maitland, A., 2010. The GeneMANIA prediction
Ferlay, J., Shin, H.R., Bray, F., Forman, D., Mathers, C., Parkin, D.M., 2010. GLOBOCAN
server: biological network integration for gene prioritization and predicting gene
2008 v2.0. Cancer Incidence and Mortality Worldwide. IARC CancerBase No. 10,
function. Nucleic Acids Res. 38 (suppl_2), W214–W220.
Lyon, France.
Wishart, D.S., Knox, C., Guo, A.C., Shrivastava, S., Hassanali, M., Stothard, P., Chang, Z.,
Ferlay, J., Colombet, M., Soerjomataram, I., Mathers, C., Parkin, D.M., Piñeros, M., Znaor,
Woolsey, J., 2006. DrugBank: a comprehensive resource for in silico drug discovery
A., Bray, F., 2019. Estimating the global cancer incidence and mortality in 2018:
and exploration. Nucleic Acids Res. 34 (suppl_1), D668–D672.
GLOBOCAN sources and methods. Int. J. Cancer 144 (8), 1941–1953.
Xia, J., Gill, E.E., Hancock, R.E., 2015. NetworkAnalyst for statistical, visual and network-
Hartmann, L.C., Sellers, T.A., Frost, M.H., et al., 2005. Benign breast disease and the risk
based meta-analysis of gene expression data. Nat. Protoc. 10 (6), 823.
of breast cancer. N. Engl. J. Med. 353, 229–237.
Yang, L., Wang, J., Wang, H., Lv, Y., Zuo, Y., Li, X., Jiang, W., 2014. Analysis and
Hartmann, L.C., Radisky, D.C., Frost, M.H., et al., 2014. Understanding the premalignant
identification of essential genes in humans using topological properties and biological
potential of atypical hyperplasia through its natural history: a longitudinal cohort
information. Gene 551 (2), 138–151.
study. Cancer Prev. Res. (Phila.) 7, 211–217.
Zuberi, K., Franz, M., Rodriguez, H., Montojo, J., Lopes, C.T., Bader, G.D., Morris, Q.,
Hartmann, L.C., Degnim, A.C., Santen, R.J., Dupont, W.D., Ghosh, K., 2015. Atypical
2013. GeneMANIA prediction server 2013 update. Nucleic Acids Res. 41 (W1),
hyperplasia of the breast—risk assessment and management options. N. Engl. J. Med.
W115–W122.
372 (1), 78–89.

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