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Review Article
Application of microarray in breast cancer:
An overview
Rajnish Kumar, Anju Sharma, Rajesh Kumar Tiwari

Amity Institute of ABSTRACT

Biotechnology (AIB),
Amity University Uttar
Pradesh (AUUP),
Lucknow, Uttar Pradesh,
India
Address for correspondence:
Mr. Rajnish Kumar,
E-mail: 12.rajnish@gmail.com
There are more than 1.15 million cases of breast cancer diagnosed worldwide annually. At present, only small
numbers of accurate prognostic and predictive factors are used clinically for managing the patients with breast
cancer. DNA microarrays have the potential to assess the expression of thousands of genes simultaneously.
Recent preliminary researches indicate that gene expression profiling based on DNA microarray can offer
potential and independent prognostic information in patients with newly diagnosed breast cancer. In this paper,
an overview upon the applications of microarray techniques in breast cancer is presented.

Received : 150811
Review completed : 060911
Accepted : 170911 KEY WORDS: Breast cancer, DNA, genome, microarray

B reast cancer in women represents a significant health

problem. Thirty percent of all cancers in women occur in
breast thereby making it the most common form of cancer.[1] In
majority of the cases, i.e., about 90% breast cancer is always due
to genetic abnormalities such as variations in high-penetrance
genes such as BRCA1, BRCA2, p53, PTEN, ATM, NBS1, LKB1,
etc.[2] In addition, the AR, ATM, BARD1, BRIP1, CHEK2,
DIRAS3, ERBB2, NBN, PALB2, RAD50, and RAD51 genes are
associated with breast cancer.[3] Only 5%-10% of cancers is due
to an abnormalities inherited from parents, either of them.
Breast cancer starting in tissues may be invasive or non-invasive.
Invasive are the ones which spread from milk duct or lobules
to other tissues in the breast while noninvasive means it has
not invaded other breast tissues. Noninvasive breast cancer is
called in situ. Therefore, two main types of cancer are; ductal
carcinoma in situ (DCIS) or intraductal carcinoma and lobular
carcinoma in situ (LCIS). Many breast cancers are also sensitive
to hormone estrogen.
Cancer cells exhibit a common phenotype of uncontrolled
cell growth, but this phenotype may arise from many different
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combinations of mutations. By inferring how cells evolve in
individual tumors, a process called cancer progression; we may
be able to identify important mutational events for different
tumor types, potentially leading to new therapeutics and
diagnostics. Work of Park et al.[1] has shown that it is possible
to infer frequent progression pathways by using gene expression
profiles to estimate "distances" between tumors. Human breast,
tumors are diverse in their natural history, is a heterogeneous
disease that comes in several clinical and histological forms.
The mechanism(s) accounting for breast cancer heterogeneity
remains elusive. Breast cancer can be grouped into major
subtypes by both histopathological features (e.g., histological
type, grade, estrogen receptor, progesterone, HER2 status)
used in diagnostic as well as newer microarray based molecular
profiling.[4,5]
A study of sporadic breast tumors samples by Perou et al.[5]
was the first to show that breast tumors could be classified
into subtypes distinguished by differences in their expression
profiles. Using 40 breast tumors and 20 matched pairs
of samples before and after doxorubicin treatment, an
intrinsic gene set of 476 genes were selected that were
more variably expressed between 40 tumors than between
the paired samples. In an interesting analysis, Chang et al.[6]
demonstrated clustering and segregation study using 78
tumors and 70 prognostic genes. On the basis of expression
levels, four major subgroups: a luminal cell-like group
expressing the estrogen receptor (ER); a basal-like group
expressing keratins 5 and 17, integrin b4, and laminin, but

How to cite this article: Kumar R, Sharma A, Tiwari RK. Application of microarray in breast cancer: An overview. J Pharm Bioall Sci 2012;4:21-6.

Journal of Pharmacy and Bioallied Sciences January-March 2012 Vol 4 Issue 1 21

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Kumar, et al.: An overview on application of microarray in breast cancer
lacking ER expression; an Erb-B2-positive group and a
normal epithelial group were identified. In another study,
Gruvberger et al.,[7] profiled 58 grossly dissected primary
invasive breast tumors and used artificial neural network
(ANN) analysis to predict the ER status of tumors on the
basis of their gene expression patterns.
Microarray Technology
Basic principle of microarray is base-pairing and hybridization
[Figure 1]. DNA microarray platforms for gene expression
profiling were invented relatively recently, and breast cancer
has been among the earliest and most intensely studied disease
using this technology. The new molecular profiling has enriched
our understanding of breast cancer heterogeneity and yielded
new prognostic and predictive information.
Four different gene lists composed of varying number of
genes have been used for molecular subtype identification
and classification of breast cancer.[8] The newer molecular
taxonomy has highlighted the existence of four major subtypes
(Luminal-A, Luminal-B, Basal-like, HER2) that overlap with
different clinical and pathological classification systems [Figure
2].[9,10] Expression profiling class discovery studies have led to
a working model for breast cancer molecular taxonomy, which
has become widely used and recently adopted for the design of
clinical trials. The molecular signatures so identified help not
only in revealing the biological spectrum of breast cancers, but
simultaneously also provide diagnostic as well as prognostic and
predictive gene signatures, and may identify new therapeutic
targets.[11] Moreover, creation of tissue microarray (TMA) allows
for the rapid immune-histochemical analysis of thousands of
tissue samples in a parallel fashion.[12] Although optimizing
treatment through microarray-based molecular subtyping is
a promising method, current application is restricted to the
prediction of distant recurrence risk.[13]
Recent Developments in Application of
Microarray in Breast Cancer
A numerous whole-genome approaches have been carried out
to identify the molecular profiles that reflect breast cancer
Figure 1: An outline of microarray methodology
22 Journal of Pharmacy and Bioallied Sciences January-March 2012 Vol 4 Issue 1
progression. The scope of prevalent whole genome profiling
efforts has encompassed on classical karyotypic analyses that
identify chromosomal rearrangements,[14] as well as gene
expression profile[15] and epigenetic studies[16,17] that provide
snap-shot signatures of gene expression and chromatin
modification patterns, respectively. In the context of breast
cancer, whole genome approaches have identified prognostic
gene sets that predict a short interval to distant metastases
(i.e., a poor prognosis signature;[18-20] and described gene profiles
that mediate metastasis to a secondary site).[21-23] However, few
reports have identified epigenetic
signatures of breast cancer, particularly in the context of
epigenetic mechanisms of tumorigenesis that could be applied
in cancer management [Table 1]. Such applications could
provide diagnostic tests, prognostic factors and predictors of
treatment response that would complement standard gene-
expression based assays.[30] Furthermore, the integration of
datasets from multiple whole genome platforms is complicated
by the interrelated nature of the genetic and epigenetic
signatures that characterize individual cells in both their normal
or tumorigenic states.[31]
Rodenhiser et al.[17] identified genome-wide DNA methylation
changes in a cell-line model of breast cancer metastasis. They
studied complex epigenetic changes, along with concurrent
karyotype analyses thereby leading to the hypothesis that
complex genomic alterations in cancer cells (deletions,
translocations, and ploidy) are superimposed over promoter-
specific methylation events that are responsible for gene-
specific expression changes observed in breast cancer
metastasis. In a recent study, Rodenhiser et al.[32] carried
out simultaneous high resolution, whole-genome analyses of
MDA-MB-468GFP and MDA-MB-468GFP-LN human breast
cancer cell lines (an isogenic, paired lymphatic metastasis
cell-line model) using Affymetrix gene expression (U133),
promoter (1.0R), and SNP/CNV (SNP 6.0) microarray
platforms to correlate data from gene expression, epigenetic
(DNA methylation), and combination copy number variant/
single nucleotide polymorphism microarrays. Many of these
epigenetic alterations correlated with gene expression changes.
This approach allows more precise profiling of functionally
Figure 2: Molecular subtypes of breast cancer and their distribution
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Kumar, et al.: An overview on application of microarray in breast cancer

Table 1: Some of gene expression signatures available for clinical use

Gene expression signature Genes Citation
Poor prognosis signature/BRCA1 carriers LASP1, TFPI, SLC7A2, TMEM98 Van't Veer et al.[15]
signature KIAA0100, MYLIP, E2F2, TRAF3IP3, NME2, GLRX2, TYMP, VIM
76-gene signature CD44, ZCCHC8, MAP4, POLQ, GTSE1, ACACB, SUPT16HP, ABLIM1, Wang et al.[18]
EEF1A2, PARP4, NEFL, ETV2, NEURL
Intrinsic/UNC signature AK2, CD38, CX3CL1, DYRK4 Hu et al.[24]
STARD3NL, BRCA1, SEMA3B, CDH1, CTNNA1, FAM120A, PTGER3,
LAMA3
Molecular prognostic index signature T17, T52, TFAP2B, ZMYND11, TGFBR3, SPAG5, RAD54L, BIRC5, CDKN3, Teschendorff et al.[25]
MYBL2
Invasiveness gene signature LTF, AGPS, SKIV2L2, GOPC, CASP8, UHRF1BP1, ATXN3, MAST4, Liu et al.[26]
NUCKS1, SLC44A1, PDE8A, NSF, NUP37
Core serum response signature WDR54, PDK2, TNFRSF12A, ETV1, PHTF2, CDKL5, CDC2L1, IL32, Chang et al.[27]
REV3L, VTA1, LYPLA2, CLCN6
Chromosomal instability signature CIN70, CIN25, MCM10, ELAVL1, TRIP13, MCM2, UNG, TPX2, KIF4A, Carter et al.[28]
CDC45L, CDC6, OIP5
Gene expression grade index HCCS, AASS, NME2, TACC3, AKAP11, SNX1, HMGB3, IFT88, RAD51, Sotiriou et al.[29]
POLQ, PIGV

Figure 3: DNA microarrays offer the capability to develop personalized therapeutic treatments by supporting clinical decision making, as well as
improving our understanding of the molecular basis of breast cancer

relevant epigenetic signatures that are associated with cancer
progression and metastasis.
A two-color microarray-based profiling platform was optimized
by Marton et al.[33] using a set of 50 fresh frozen (FF) breast
cancer samples. Veer et al.[15] assigned class labels according to
the signature and method. They proved that profiling platform is
able to accurately sort formalin fixed paraffin embedded tissues
(FFPET) samples into class labels derived from FF classifiers.
Furthermore, using this platform, a classifier derived from
FFPET samples can reliably provide the same sorting power
as a classifier derived from matched FF samples. Lih et al.[34]
study paves the way to identify novel molecular biomarkers
for disease stratification and therapy response from archival
FFPET samples, leading to the goals of personalized medicine
[Figure 3]. Fixed in formalin and embedded in paraffin (FFPE),
tissues are the most commonly available clinical samples with
documented clinical information for retrospective clinical
analysis. However, till date there has been limited application
of microarray- based gene expression analysis to FFPET.
Tissue samples collected during surgery as well as biopsies are
often FFPE. Molecular genomics assays on archived FFPE
blocks, together with clinicopathological information, can
provide critical insights into a heterogeneous disease such
as breast cancer. Gene expression profiling of FFPE samples
represents great potential for translational cancer research.[35,36]
Formalin preserves tissue and cellular structure by cross-linking
proteins and macromolecules.[37] Unfortunately, this type of
analysis has proven to be problematic because of the poor
quality of RNA extracted from FFPE. Microarray expression
analysis using FFPE tissues has been problematic as the
retrieval of RNA from FFPE material is challenging.[38] FFPE
archival methods lead to chemical modifications (methylene
dimerization ormonomethylolation) and the partial degradation
of the RNA (up to 50% of the RNA may not contain an intact
poly-A tail),[38,39] making RNA extraction, reverse transcription
and quantitation a difficult process. Formalin-fixed (FF) tissues
have been shown to yield compromised RNA compared with
that obtained from frozen tissue. Currently, several prognostic
microarray gene expression signatures for breast cancer have
been generated using fresh frozen material.[40]
Lih et al.,[34] used a novel RNA amplification method, Single
primer isothermal amplification (SPIA) to amplify FFPET
RNA, which was hybridized amplified, and labeled cDNA onto

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Kumar, et al.: An overview on application of microarray in breast cancer
Affymetrix HG U133plus2 GeneChips.It was observed that
SPIA amplification successfully overcomes the problems of poor
quality of FFPET RNA, and produced informative biological
data. Comparison of gene expression data from five different
types of FFPET archival cancer samples (breast, lung, ovarian,
colon, and melanoma), demonstrated that gene expression
signatures clearly distinguish the tissue of origin. Further, from
an analysis of 91 FFPET samples comprised of ER+, HER2+,
triple negative breast cancer patients, and normal breast
tissue, they identified a 103 gene signature that distinguishes
the intrinsic subtypes of breast cancer. The accuracy of gene
expression measured by microarray was verified by real time
PCR quantization of the ERBB2 gene, resulting in a significant
correlation (R = 0.88).
Zhou et al.[41] developed dissociable antibody microarray
(DAMA) staining technology that combines protein
microarrays with traditional immune-staining techniques
and demonstrated its application in identifying potential
biomarkers for breast cancer. DAMA can simultaneously
determine the expression and subcellular location of hundreds
of proteins in cultured cells and tissue samples. They compared
the expression profiles of 312 proteins among three normal
breast cell lines and seven breast cancer cell lines and identified
10 differentially expressed proteins by the data analysis
program DAMAPEP (DAMA protein expression profiling).
Among the investigated proteins, RAIDD, Rb p107, Rb p130,
SRF, and Tyk2 were confirmed by Western blot and statistical
analysis to have higher expression levels in breast cancer cells
than in normal breast cells and therefore concluded that these
proteins could be potential biomarkers for the diagnosis of
breast cancer.
Glass et al.[42] demonstrated for the first time that microarray
technology can be used as a reliable diagnostic tool. They
established 70-gene tumor expression profile, on microarrays
containing 25,000 60-mer oligonucleotides, as a powerful
predictor of disease outcome in young breast cancer
patients. Bose et al.[43] studied the status of Akt pathway
in human breast cancers and relationship with different
component proteins. Expression levels of phosphorylated
form of constituent proteins and cyclin D1 were evaluated by
immunohistochemistry, on consecutive sections from a tissue
microarray containing 145 invasive breast cancers and 140 pure
ductal carcinomas in situ.
Various groups have explored the power of expression profiling
using cDNA or DNA microarrays for distinguishing subgroups
of breast cancers.[44-46] Meta-analysis of independent microarray
datasets generated with the common objective of identifying
differentially expressed genes in a certain type of cancer has
also been performed for breast cancer. In a very recent meta-
analysis study, Smith et al.[47] identified differentially expressed
genes between ER+ and ER-- breast tumors by gathering nine
independent breast cancer microarray studies. Another study
used the power of meta-analysis to find out the relation of
expression patterns of gene and chromosomal positions. More
than 1200 breast tumors were collected from eight independent
breast studies and candidate metastasis suppressor and
24 Journal of Pharmacy and Bioallied Sciences January-March 2012 Vol 4 Issue 1
promoting genes were found from a given set of chromosomal
regions.[48] Similarly, Hu et al.[24] were able to identify a new
intrinsic gene-set for breast cancer subtype prediction by
combining multiple microarray datasets to assess prognosis.
Several different meta-analysis approaches exist in the literature.
In some, each individual study contributes rather independently
to the meta-analysis[49-51] whereas in others the values are treated
as members of a single study thus requiring a generalized
normalization step.[52] In a recent study Dedeoglu et al.[53]
developed resampling-based meta-analysis strategy, which
involves the use of resampling and application of distribution
statistics in combination to assess the degree of significance
in differential expression between sample classes. They used
two independent microarray datasets that contain normal
breast, invasive ductal carcinoma (IDC), and invasive lobular
carcinoma (ILC) samples for study. Expression of the genes,
selected from the gene list for classification of normal breast
samples and breast tumors encompassing both the ILC and IDC
subtypes were tested on 10 independent primary IDC samples
and matched nontumor controls by real-time qRT-PCR. Direct
comparison of gene expression values from multiple studies may
be relatively more problematic than comparing the effect size
obtained from individual studies. Yet, the analysis of combined
raw data is beneficial when sample sizes of individual studies
are small.
Microarray-based Online Platforms for Breast
Cancer
Recently, various microarray-based online tools have been
developed with promises of assistance to the treatment decisions
for breast cancer patients. Gene expression-based Outcome for
Breast cancer Online (GOBO) is one of newly developed online
tool.[54] GOBO has three main applications: Gene Set Analysis
(GSA), Coexpressed Genes (CG), and Sample Prediction (SP).
Recurrence online is another online tool for microarray-based
breast cancer diagnosis. It is an online analysis tool to determine
breast cancer recurrence and hormone receptor status using
microarray data. It also has three major applications: prediction
of response to hormonal treatment (ER status), prediction of
response to targeted therapy 9HER2 status) and estimation of
survival (recurrence score) for breast cancer patients.[55] Kaplan-
-Meier Plotter (KM Plotter) is online tool for the preliminary
biomarker assessment. It has two applications: KM plotter for
breast cancer and KM plotter for ovarian cancer. Prognostic
value of a particular gene can be analyzed by splitting the
patient sample into two groups according to various quantile
expressions of the proposed biomarker. Comparison can be
made between the two patient cohorts in terms of relapse free
survival or overall survival. KM plotter displays survival curve,
the hazard ratio with 95% confidence intervals and log-rank P
value as output.[56]
Conclusion
The molecular basis of breast cancer has been redefined over
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the past decade. Paving the way in this respect has been the
advent of DNA microarray technology, which has provided
a massive source of data on gene expression alterations in
human breast tumors. Microarray profiling has, unquestionably,
been established as a powerful tool in unraveling mechanistic
insights into tumor biology. The initial studies have been
promising enough to provide a novel, personalized dimension
to the treatment and care of breast cancer patients; however,
development of predictive signatures within the dimension of
molecular subtypes is an area requiring further investigation.
To conclude, researchers need to employ an array of different
technologies and utilize the whole spectrum of biological and
clinical data available in order to elucidate and clarify the
multifaceted complexity of breast cancer.
Acknowledgment
We are deeply grateful to Mr. Aseem Chauhan, chairman of Amity
University Uttar Pradesh- Lucknow Campus for providing us necessary
facilities and support. We would also like to extend our gratitude to Maj.
Gen. K.K Ohri, AVSM (Retd.), Director General of Amity University,
Uttar Pradesh- Lucknow Campus for providing us valuable guidance
and encouragement throughout the work.
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Source of Support: Nil, Conflict of Interest: None declared.

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26 Journal of Pharmacy and Bioallied Sciences January-March 2012 Vol 4 Issue 1

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