Int J Clin Exp Pathol 2018;11(3):1146-1156

www.ijcep.com /ISSN:1936-2625/IJCEP0069951

Original Article
Bioinformatic analysis of differential
expression and core GENEs in breast cancer
Hongchang Dong1*, Shuai Zhang1*, Yu Wei2*, Chunyan Liu2, Na Wang1, Pan Zhang1, Jingling Zhu1, Jin Huang1
1
The Key Laboratory of Xinjiang Endemic & Ethnic Diseases and Department of Biochemistry, Shihezi University
School of Medicine, Shihezi, Xinjiang, China; 2The First Affiliated Hospital of Medical College of Shihezi University,
Shihezi, Xinjiang, China. *Equal contributors.
Received November 27, 2017; Accepted December 22, 2017; Epub March 1, 2018; Published March 15, 2018

Abstract: Breast cancer (BRCA) is one of the most common malignancies in women. The gene expression profile
of GSE103512 from the GEO database was downloaded in order to find key genes involved in the occurrence and
development of BRCA. 75 samples, including 65 cancer and 10 normal samples, were included in this analysis.
Differentially expressed genes (DEGs) between BRCA patients and health people were chosen using R tool. We next
performed gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis us-
ing the Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, Cytoscape with Search
Tool for the Retrieval of Interacting Genes (STRING) was utilized to visualize protein-protein interaction (PPI) of these
DEGs. The related genes and medicines specific to hub genes were predicted by CBioportal. We screened a total
of 357 DEGs including 77 up-regulated and 280 down-regulated. A series of BRCA related GO terms and pathways
were identified by analysis of these DEGs. Insulin-like growth factor 1 (IGF1); epidermal growth factor receptor
(EGFR); v-jun avian sarcoma virus 17 oncogene homolog (JUN) and Estrogen Receptor 1 (ESR1) of the DEGs were
screened by construction of the PPI network and the degree of connectivity. IGF1 and ESR1 were finally selected as
potential hub genes and treatment targets of BRCA. In conclusion, this bioinformatics analysis demonstrated that
DEGs and hub genes, such as IGF1, might regulate the development of gastric cancer. These DEGs could be used
as new biomarkers for diagnosis and to guide the combination medicine of BRCA.

Keywords: Breast cancer, bioinformatics analysis, differential expression genes, biomarker, therapeutic

Introduction recent years show that with the development

of industrialization and the change of people’s
Breast cancer is currently the main cause of lifestyle, the overall incidence of breast cancer
death among women in the world [1]. Although is increasing and the age of onset is decreasing
the mortality of breast cancer has decreased, [7, 8]. However, current diagnostic technolo-
owing to the development of modern therapeu- gies, including imaging, molecular detection,
tic approaches, the morbidity is still very high and immunohistochemistry (IHC) have inherent
[2]. About 1,700,000 new cases of breast can- limitations and may provide uncertain results
cer and 521,900 deaths every year have been [9, 10]. Thus, the early diagnosis and treatment
reported worldwide [3]. In China, especially in of breast cancer are becoming more and more
rural areas where people have lower income important.
and less access to health care facilities, the
morbidity of breast cancer has reached 24.20 Recently, many biomarkers and therapeutic
per 100,000 [4]. In the United States, 231,840 target genes have emerged. Estrogen receptor
women were diagnosed with and 40,290 died (ER), progesterone receptor (PR), human epi-
from breast cancer in 2015 [5]. Women of dermal growth factor receptor-2 (HER2), and
African descent show a lower incidence, but proliferation marker Ki-67 have been used to
higher mortality rates and earlier age of onset identify the subtypes and diagnose the breast
[6]. Although China is a low-lying area relative cancer [2]. The most common treatment strate-
to western countries, epidemiological data in gies today are endocrine therapy, chemothera-
 Core genes in breast cancer development

Table 1. DEGs with P < 0.01 and |logFC| > 1

EXPRESSION GENE SYMBOL
Down-regulated HBA2///HBA1 HBA2///HBA1 LYVE1 ADH1B
HSPB6 HBB FABP4 PDK4 ADH1B CD36 CD36 HSPB6 HBA2///HBA1 CD36 PLIN1 CCL15-CCL14///CCL15///CCL14 HBA2///HBA1 FHL1 FHL1
LPL LYVE1 HBB GPX3 FOS CD36 FOSB FHL1 PDK4 NTRK2 PLA2G2A IGF1 SRPX IGSF10 IGF1 DPT TNXB///TNXA TWIST2 CCL18 GPX3N PIGR
ADIPOQ EFEMP1 CXCL12 FHL1 FHL1 TFPI OGN FABP4 ALPL MMP19 PTGIS NTRK2 MT1M DST ENPP2 PDK4 CIDEC ABCA6 PIGR ADAMTS5
EGR1 PTGDS
SVEP1 DPT MEG3 CD209 HBB IGFBP6 SYNM CFD ALPL PTGIS CCL18 CAV1 C2orf40 MEG3 AOC3 SAA2///SAA1 MATN2 OGN SOCS3 PTGIS
NTRK2 LINC01279 MYH11 ABCA8 VIM CCL28 SAA2///SAA1 CXCL2 ADAM33 EGR1 ANXA1 TGFBR3 TNXB///TNXA CCDC80 GALNT16
KIT CAV1 COL14A1 TFPI ENPP2 DUSP1 FAM126A CRISPLD2 SLIT3 SCARA5 EBF1 IGF1 MEG3 BTNL9 CHRDL1 RHOJ OSR1 ITM2A IGF1 CAPN6
TNXB///TNXA CCL21 CEBPD MFAP4 CCL28 KLF4 PALMD CCDC80 COL14A1 SOD3 RGCC MYH11 TNXB ACACB SAMD5 SVEP1 ANK2 MYH11
MAO APDGFRA LRRN4CL G0S2 ANXA1 SYNPO2 TSHZ2 TFPI SCARA5 CCDC80 PLTP ABCA9 SLC16A7 DUSP1 PTGDS MEST KLF4 EBF1 EMP1
ABI3BP PLPP3 COL14A1 DST PTGDS CXCL2 SOD2 PALMD RUNX1T1 JUN RHOJ PDGFD PLPP3 PDGFD TGFBR2 RHOJ ACACB JUN ANK2 C7
EDNRB ACACB AOX1 F13A1 PCDH18 CD248 EBF1 DPT ITM2A ZFP36 GAS1 LPL
ADAMTS1 LIFR PLPP3 SNORD114-3 RHOJ ADD3 TGFBR3 AQP1 ITIH5 EGFR COL14A1 CXorf36 GPAM CLEC3B C1R MYH11 CDR1 CCL13 MED-
AG SVEP1 ADGRA2 AOX1 FMO2 ATF3 CFHR1///CFH SYNPO2 TNXB FIGF LDB2 RND3 FLRT2 TTN ADAMTSL4 CD209 EDNRB RHOU APCDD1
TNS1 CD163 GAS7 IGHD TBX18 MS4A4A KCNIP2 SYNPO2 AQP1 TNS1 PLIN4 ADGRA2 CD34 PRNP RHOJ TBX18 CNN1 DCLK1 ADAMTS5
ADD3 GNG11
FMO2 PROS1 EFEMP1 LHFP RSPO3 ADAMTS5 KLF2 CAPN6 LILRB5 LINC00341 KCNMB1 TF RCAN1 ANGPTL2 CLDN11 ADD3 CD163 CO-
L15A1 CDC42EP5 PER1 MS4A4A GPM6B ISM1
Up-regulated INTS7 IRX5 SBK1 MSI2 F11R SDC1 DDR1 EPS8L2 SYNE4 CERS6 F7 MSI2
MYO6 RAB25 CAMSAP3 FKBP4 DHTKD1 PLEKHF2 HACD3 FAM83H HN1L
STRBP SPINT1 IQGAP3 LLGL2 PMEPA1 GRHL2 DDR1 PRR5 DNAH14 CST4
CYTH2 UBE2C HSPA1B///HSPA1A CERS6 ESRP1 ELF3 MSI2 HN1L MAL2
ESYT2 SRP9 KDM4B DDR1 PRSS8 ERBB3 TFAP2A INHBA TPD52 ERBB3
ERBB3 TRPS1 KIFC2 TPD52 MMP11 KRT8 PARD6B SULF1 CELSR1 PRLR
SULF1 STARD10 TRPS1 KRT18 ESRP1 LOC692247 TPD52 NPNT COL11A1
MUC1 GPRC5A COL10A1 COL11A1 COL10A1 ESR1

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 Core genes in breast cancer development

py, and targeted therapy using antibodies rec- Genomes (KEGG) is a collection of databases
ognizing cancer biomarkers; however, they are dealing with genomes, biological pathways, dis-
not always successful and may cause adverse eases, drugs, and chemical substances [16].
effects and drug tolerance [11, 12]. Therefore, DEGs from GSE were uploaded to DAVID to per-
there is a constant need to investigate the form the BP (biological process), CC (cellular
development mechanism for breast cancer component), MF (molecular function) and path-
diagnosis and therapy. way enrichment analysis. P < 0.05 was set as
the cut-off criterion.
High throughput sequencing is increasingly be-
ing widely used and it has been a very signifi- PPI network construction and core genes
cant tool for life sciences, such as cancer grad- analysis
ing, cancer early diagnosis, and prognosis pre-
diction [12]. In this study, to further understand The STRING database (http://string-db.org) ai-
breast cancer, the GSE103512 was download- ms to provide a critical assessment and inte-
ed from GEO datasets and analyzed by R bio- gration of protein-protein interactions, includ-
conductor for DEGs. Analysis of the biological ing direct (physical) as well as indirect (func-
process (BP), molecular function (MF), cellular tional) associations [17]. DEGs from GSE103-
component (CC), and KEGG pathways of the 512 were uploaded to STRING for the known
DEGs and three modules were performed. The and predicted interactions analysis (confidence
regulatory network of these DEGs was con- score ≥ 0.15, maximum number of interactors
structed using string and the key genes with = 0). Next, the result was imported to Cytoscape
high degree of connectivity were selected by for the core genes screening with degree cutoff
Cytoscape. Finally, the correlation between = 25 [18].
genes, survival, and disease was confirmed
based on Kaplan Meier plotter online database Survival analysis of key genes
(http://kmplot.com/analysis/) [13] and TCGA
database. To assess the effect of 54,675 genes on sur-
vival using 10,461 cancer samples, 5,143 bre-
Materials and methods ast, 1,816 ovarian, 2,437 lung and 1,065 gas-
tric cancer patients with a mean follow-up of
Data source and DEGs identification
69/40/49/33 months [19] were analyzed. The
The GSE103512 datasets including 65 breast primary purpose of the tool is as a meta-analy-
cancer with 10 matched normal; 57 colorectal sis based biomarker assessment [19]. In this
cancers with 12 matched normal; 60 non-small study, key genes (ESR1, IGF1, EGFR, JUN) were
cell lung cancers with 9 matched normal; 60 assessed for their effect on survival with 95%
prostate cancers with 7 matched normal, was confidence intervals and log rank P value <
downloaded from GEO. The breast cancer data 0.01.
were chosen to perform the differential expres-
sion genes analysis. The Bioconductor package Correlation between hub genes and breast
of R was applied to detect the DEGs with cut-off cancer
criteria (adjust P value < 0.01 and |logFC| ≥ 1)
[14]. A total of 357 genes with significant dif- Study on the correlation between hub genes
ferential expression were selected after the and breast cancer was performed by the online
analysis of GSE103512; of which, 77 were up- tools GEPIA (http://gepia.cancer-pku.cn/index.
regulated genes and 280 were down-regulated html). GEPIA is a web server for analyzing the
(Table 1). RNA sequencing expression data of 9,736
tumors and 8,587 normal samples from the
Gene ontology and KEGG pathway enrichment TCGA and the GTEx projects, using a standard
analysis processing pipeline [20].

To identify characteristic biological alterations Medicine and regulatory factors of hub genes
in high throughput genome and transcriptome prediction
data, gene ontology analysis (GO), an online
tools containing numerous database, is a usual CBioPortal (http://www.cbioportal.org/) web-
method for annotating genes and gene prod- site integrates the data of 126 tumor genome
ucts [15]. Kyoto Encyclopedia of Genes and research, including TCGA and ICGC, covering

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 Core genes in breast cancer development

Figure 1. DEG screening of GSE 103512 datasets. Cassette figures before (A) and after (B) data standardization.
(C) Hierarchical clustering of the first 150 DEGs. The color scale shown at the top illustrates the relative expression
level of an mRNA. Red color represents a high relative expression level and a green color represents a low relative
expression level.

the data of twenty-eight thousand specimens. set the adjust P value < 0.01 and |logFC| ≥ 1 as
Here we used this website for prediction of cut-off criteria. The alignment of black dots on
medicine and regulation factors of hub genes the same line indicates good standardization.
based on such database including Phospho- Analysis of the mRNA expression fold-change of
Site, KEGG Drugs, pid, HumanCyc, Reactome, the DEGs showed a highly significant difference
PANTHER and DrugBank [21]. between BRCA and normal tissues (Figure 1C).
These results revealed that the data can be
Results directly used for further analysis. Finally, a to-
tal of 357 differential expressed genes were
Screening of DEGs detected after the analysis of GSE103512, of
which 77 were up-regulated genes and 280
To observe the alteration between breast can- were down-regulated (Table 1).
cer and normal tissues on the transcriptome
level, 65 breast cancer and 10 matched normal Identification of GO terms and pathways re-
mRNA expression values of GSE103512 datas- lated to DEGs
ets were analyzed by R conductor package.
Cassette figures before (Figure 1A) and after The Database for Annotation, Visualization and
(Figure 1B) data standardization are shown. We Integrated Discovery is an online bioinformatics
1149 Int J Clin Exp Pathol 2018;11(3):1146-1156
 Core genes in breast cancer development

1150 Int J Clin Exp Pathol 2018;11(3):1146-1156

 Core genes in breast cancer development

Figure 2. GO and KEGG pathway analysis of DEGs using-log p. A. Analysis of molecular function enrichment. B.
Analysis of biological process enrichment. C. Analysis of cellular component enrichment. D. Analysis of KEGG path-
way analysis.

Figure 3. PPI network construction of DEGs. The yellow node in the network represents the core node with degree
≥ 25.

resource that provides tools for the functional cancer development, we constructed the regu-
enrichment of large lists of genes or proteins latory network by analysis of PPI and then IGF1
[22]. To better understand breast cancer devel- (degree = 36), EGFR (degree = 36), JUN (degree
opment, molecular function (Figure 2A), bio- = 33), ESR1 (degree = 34) were selected as the
logical process (Figure 2B), cellular component hub genes (Figure 3).
(Figure 2C) and signaling pathway (Figure 2D)
alteration in the disease were analyzed by IGF1 and ESR1 alterations may play important
DAVID. role in breast cancer patient’s survival

PPI network analysis reveals the hub genes Survival analysis is widely used in clinical and
among DEGs epidemiological research, in randomized clini-
cal trials for comparing the efficacy of treat-
The potential main regulators may be the focal ments, and in observational (non-randomized)
point for therapeutic and drug design. In this research to determine and test the existence of
analysis, 77 up-regulated and 280 down-regu- epidemiological association [22]. In our study,
lated genes were selected based on our crite- survival analysis was performed to assess the
rion. To obtain the core genes during breast hub genes in patient’s survival. The results sug-

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 Core genes in breast cancer development

Figure 4. Prognostic value of four genes (IGF1 (A), ESR1 (B), JUN (C), EGFR (D)) in BRCA patients. The desired
Affymetrix IDs are valid: 209541_at (IGF1), 201464_x_at (ESR1), 202311_s_at (JUN), 1565483_at (EGFR). HR:
hazard ratio, CI: confidence interval.

gest that expression of IGF1 (HR = 0.75 (0.68- grated PhosphoSite, KEGG Drugs, pid, Human-
0.84) log rank P = 4.2e-07) (Figure 4A) and Cyc, Reactome, PANTHER, and DrugBank data-
ESR1 (HR = 0.67 (0.6-0.74) log rank P = 2.5e- bases, to analyze genes and drugs. In our
13) (Figure 4B) but not JUN (HR = 0.88 (0.79- results, 37 FDA approved drugs and 41 non-
0.98) log rank P = 0.02) (Figure 4C) and EGFR FDA approved drugs were selected for ESR1.
(HR = 0.87 (0.74-1.01) log rank P = 0.074) Only Deoxy-Bigchap was selected for IGF1
(Figure 4D) was associated with worse overall (Figure 6). There were also many proteins that
survival (OS) for breast cancer patients. To could regulate IGF1 and ESR in transport, phos-
determine the correlation between hub genes phorylation, expression, and other potential
and breast cancer, IGF1, and ESR1 expression ways (Figure 6).
was evaluated by GEPIA. Indeed, expression of
IGF1 (Figure 5A) was down-regulated and ESR1 Discussion
(Figure 5B) was up-regulated in breast cancer.

Various genes and medicines specific to IGF1 Approximately 232,340 new cases of invasive
and ESR1 reveal IGF1 and ESR1 as potential breast cancer and 39,620 breast cancer dea-
targets for breast cancer treatment ths are expected to occur among US women in
2013. Although exemestane is currently appro-
To evaluate if IGF1 and ESR1 could be targets ved by the US Food and Drug Administration to
for breast cancer therapeutics, a website inte- prevent breast cancer recurrence, promising

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 Core genes in breast cancer development

cating the association of

these GO term and breast
cancer. In the cellular com-
ponent analysis, most of
these DEGs were enriched
in GO terms such as extra-
cellular space, extracellular
region, proteinaceous ex-
tracellular matrix, extracel-
lular exosome, extracellular
matrix, cell surface, apical
plasma membrane and
membrane raft, etc. These
GO terms are totally associ-
ated with membranes and
suggest that secreted pro-
tein and membrane protein
reactions such as some
receptors and ligands inter-
action may play important
roles in the breast cancer
progression. Coincidentally,
Figure 5. Expression level of IGF1 (A) and ESR1 (B) in cancer and normal tis- this speculation was asse-
sues. BRCA: breast cancer, T: tumor tissues, N: normal tissues, *P < 0.05.
ssed in the KEGG pathway
analysis which contains the
results from clinical trials led the American cytokine-cytokine receptor interaction term.
Society of Clinical Oncology to include exemes- Other pathways in our study may also associate
tane in their guidelines as a third option for che- with breast cancer development.
moprevention [23]. Continued progress in the
control of breast cancer will require sustained As the protein and protein interaction maybe
and increased efforts to provide high-quality essential for breast cancer, the PPI network of
screening, diagnosis, and treatment to all seg- DEGs was constructed using STRING in our
ments of the population. research. This data shows us a complicated
regulation network in the breast cancer. But
Biomarker identification for any disease helps there should be some hub genes for breast
in the development of improved diagnostics cancer therapeutics, therefore, the core node
and clinical treatment efficacy. Microarray data with high connective degree was selected by
analysis has been widely used for disease bio- Cytoscape. With this approach, 4 genes includ-
marker discovery [23-26]. In this study, gene ing IGF1, EGFR, ESR1 and JUN were selected
transcription alteration of breast cancer and for our analysis.
normal in GSE103512 was analyzed. 77 up-
regulated and 280 down-regulated DEGs were To assess the results of our analysis, survival
observed including an usual biomarker ESR1 in analysis and expression comparison of the 4
BRCA. These results indicate that these DEGs genes was executed based on TCGA and other
may be biomarkers of breast cancer. To have a cancer databases. EGFR and JUN were without
better understanding of the biological contribu- a significant effect on patient’s survival and
tion of these DEGs, MF, and BP analysis were were excluded in our study. Studies have shown
executed. The response to cAMP, extracellular that diabetes is a risk factor for breast cancer
matrix organization, positive regulation of gene development and is associated with poor prog-
expression, cell chemotaxis, cell adhesion of nosis for breast cancer patients [27]. IGF1, a
BP and heparin binding, calcium ion binding, polypeptide protein similar to insulin molecular
transmembrane receptor protein tyrosine kina- structure, its precursor could induce breast
se activity, transcription factor activity, RNA cancer cell proliferation via the IGF1 receptor
polymerase II core promoter proximal region [28]. However, there was no direct evidence for
sequence-specific binding were identified, indi- the effect of IGF1 on breast cancer diagnosis

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 Core genes in breast cancer development

Figure 6. Medicine and regulatory factors of IGF1 and ESR1 prediction. Pink circles: genes, white hexagon: drugs
not approved by FDA, yellow hexagon: FDA approved drugs, Pink arrows: transport controls, turquoise arrows: phos-
phorylation controls, green arrows: controls expression, yellow lines: targeted by drug.

and therapeutics. Here, we demonstrate that peutics. Screening of these drugs should be
the mRNA level of IGF1 was significantly de- performed. The genes that regulate ESR1 tran-
creased between BRCA tumor and normal tis- sport, phosphorylation, expression, and other
sues and seemed to be the core factor among potential ways may also participate in the
these DEGs. There are many studies that have human self-protection against BRCA.
shown that mutation of ESR1 was essential for
breast cancer and this gene has been applied Our bioinformatics analysis identified DEGs
as a breast cancer biomarker [2, 3, 29]. It also that might play a central role in the occurrence,
indicated the effectiveness of our analysis. In development, and prognosis of breast cancer.
addition, the breast cancer patients in our In this study, a total of 357 DEGs were selected,
study are ESR1 high expressers, but it is inter- and EGFR, JUN, IGF1, and ESR1 might be the
esting that breast cancer patients with high core genes of breast cancer. In order to get
ESR1 present higher survival than low ESR1 more accurate correlation results, we perform-
expression. We suspect this phenomenon is a ed a series of verification experiments later to
self-protection mechanism against breast can-
confirm the results of this prediction. Finally,
cer and deserves experimental verification.
IGF1 and ESR1 were selected as hub genes for
We also predict the potential drugs for breast diagnosis and treatment of breast cancer.
cancer therapeutics according to our analysis, Overall, this study provides some powerful evi-
and this also highlights the potential of IGF1 dence for future genomic individualized diagno-
and ESR1 as targets of breast cancer thera- sis and treatment of breast cancer.

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 Core genes in breast cancer development

Acknowledgements China: a population-based case-control study.

PLoS One 2017; 12: e0184453.
We are grateful to Brouwer-Visser J, Cheng W, [9] Lindenberg MA, Miquel-Cases A, Retel VP, Son-
Bauer-Mehren A, Maisel D, Lechner K, Ander- ke GS, Wesseling J, Stokkel MPM and van
sson E, Dudley JT, Milletti F who provided the Harten WH. Imaging performance in guiding
response to neoadjuvant therapy according to
GSE103580 dataset for this analysis, and it is
breast cancer subtypes: a systematic literature
our pleasure to acknowledge their contribu- review. Crit Rev Oncol Hematol 2017; 112:
tions. This study was supported by the National 198-207.
Natural Science Foundation of China (No. [10] Gunn S YH, Sims C, Govender S, Moore M, Cot-
81771173 and 31060136). ter P, Jones S. A clinically validated DNA micro-
array for high-resolution HER2 testing defines
Disclosure of conflict of interest a new genomic subtype in high-risk breast can-
cer with equivocal results by IHC and FISH.
None. Cancer Res 2017; 77: 9.
[11] Harbeck N and Gnant M. Breast cancer. Lan-
Address correspondence to: Dr. Jin Huang, The Key cet 2017; 389: 1134-1150.
Laboratory of Xinjiang Endemic & Ethnic Diseases [12] Kulasingam V and Diamandis EP. Strategies
and Department of Biochemistry, Shihezi University for discovering novel cancer biomarkers th-
rough utilization of emerging technologies. Nat
School of Medicine, Shihezi 832002, Xinjiang, Chi-
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na. Tel: +86-(993) 205-7882; E-mail: huangjin623@
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