WJ E M World Journal of

Experimental Medicine
Online Submissions: http://www.wjgnet.com/esps/ World J Exp Med 2012 October 20; 2(5): 86-91
[email protected] ISSN 2220-315X (online)
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/wjem.v2.i5.86 © 2012 Baishideng. All rights reserved.

EDITORIAL

Breast cancer and protein biomarkers

Lay-Harn Gam

Lay-Harn Gam, School of Pharmaceutical Sciences, Universiti

Sains Malaysia, 11800 USM, Penang, Malaysia INTRODUCTION
Author contributions: Lay-Harn Gam solely contributed to this Breast cancer is one of the leading causes of death
paper. among women[1]. It accounts for approximately 40 000
Correspondence to: Lay-Harn
�������������� ����������� School of
Gam, Professor,
deaths in the United States annually and still imposes a
Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM,
Penang, Malaysia. [email protected] significant healthcare burden on women worldwide[2].
Telephone: +60-4-6533888 Fax: +60-4-6570017 Cancer is a disorder of cells caused by an unpredict-
Received: January 10, 2012 Revised: June 28, 2012 able genetic disorder[3] which leads to growth that is vis-
Accepted: October 7, 2012 ible as a tumor[4]. It is typically considered as a disease
Published online: October 20, 2012 of aging because the chances of developing this disease
increase with age[5]. Cancer is characterized by uncon-
trolled cell proliferation, disruption of apoptosis, sus-
tained angiogenesis and increased cell ability to invade
Abstract other tissues and metastasize[6,7]. Today, cancer is one of
the main causes of global mortality.
Breast cancer is a healthcare concern of women world-
A biomarker is a biochemical substrate that indicates
wide. Despite procedures being available for diagnosis,
a physiological state or development of a disease[8]. It
prognosis and treatment of breast cancer, research-
is usually a biological substance found in blood, tissue
ers are working intensively on the disease in order to
or other body fluids. Useful biomarkers should have
improve the life quality of breast cancer patients. At
a strong association with the outcome of the disease.
present, there is no single treatment known to bring
a definite cure for breast cancer. One of the pos-
Among the common clinical usage of biomarkers are
sible solutions for combating breast cancer is through the diagnosis, prognosis, treatment and indicators for the
identification of reliable protein biomarkers that can risk of developing the disease[9]. In the context of the
be effectively used for early detection, prognosis and disease’s treatment, a biomarker whose expression levels
treatments of the cancer. Therefore, the task of iden- change according to treatment can be used to determine
tification of biomarkers for breast cancer has become the progress of the treatment[10]. The presence of a spe-
the focus of many researchers worldwide. cific biomarker is often used as an indicator to predict
the response of patients to therapy [11]. Nevertheless,
© 2012 Baishideng. All rights reserved. before a biomarker can serve its purpose, a thorough
evaluation of its reliability needs to be validated.
Key words: Breast cancer; Protein; Biomarkers; Pro-
teomics
CANCER BIOMARKERS
Peer reviewer: Javier Camacho, PhD, Centro de Investigación Cancer biomarkers can be classified as cellular and
y de Estudios Avanzados del IPN, Department of Pharmacol- humoral markers. A cellular marker is associated with
ogy, Avenida Instituto Politécnico Nacional 2508, CP 07360 cancer cells and therefore it provides prognostic infor-
Mexico City, México mation for the patient from which a therapeutic plan
suit best to the patient can be determined[12,13]. On the
Gam LH. Breast cancer and protein biomarkers. World J Exp
other hand, a humoral cancer marker is characterized
Med 2012; 2(5): 86-91 Available from: URL: http://www.
wjgnet.com/2220-315X/full/v2/i5/86.htm DOI: http://dx.doi.
by its detection in body fluids. It is secreted either by
org/10.5493/wjem.v2.i5.86
the tumor or during tumor disintegration[13]. A humoral
cancer marker is useful in the early detection of cancer,

WJEM|www.wjgnet.com 86 October 20, 2012|Volume 2|Issue 5|

 Gam LH. Breast cancer and protein biomarkers

especially in asymptomatic people with high risk of de- of both sensitivity and specificity as a marker for early
veloping cancer[12]. stage disease. However, its specificity can be improved
In terms of the usage of biomarkers, cancer bio- by combining CA-125 with various forms of sonogra-
markers can be divided into three main categories, phy[14]. Changes in serum protein levels may also indicate
namely diagnostic, prognostic and predictive biomarkers. the response of patients to chemotherapy in HER2-
A diagnostic marker is used to detect the presence of the positive breast cancer patients, where a few serum based
disease. A prognostic marker is used after the establish- proteins, namely alpha-2-macroglobulin, complement 3,
ment of the disease status to predict the course of the hemopexin and serum amyloid P, can be used as indica-
disease and its recurrence and can be used to indicate the tors for patients’ positive response to chemotherapy[25].
aggressiveness of the tumor. A predictive marker is used Prediction of patients’ response to drugs is important
to predict the likely response of a patient to a drug prior for effective cancer treatment. Recently, many predictive
to a treatment so that patients are classified as “respond- biomarkers have been suggested for different types of
er” or “nonresponder” by the presence or absence of the drug treatment. Estrogen receptor (ER) and proges-
marker. Such a prediction is important in designing clini- terone receptor are useful indicators for prediction of
cal drug trials to define the intended use of the drug[14]. breast cancer patients’ responses to hormonal therapy
in an adjuvant setting and metastatic disease. Heat shock
protein 70 showed significant positive correlation for the
CURRENTLY AVAILABLE BREAST usage of aromatase inhibitors in hormonal therapy[26]. As
CANCER BIOMARKERS for ER-positive breast cancer, truncated BH3 interacting
There are a few potential serum based biomarkers for domain death agonist[27] and 14-3-3 proteins, including
breast cancer. Nevertheless, only two of the serum based theta/tau, gamma, epsilon, beta/alpha and seta/delta
biomarkers were approved by the Food and Drug Ad- isoforms, can be used as indicators for patients’ re-
ministration (FDA) for monitoring and treatment of the sponses to neoadjuvant chemotherapy[28]. In the event of
advanced or recurrence breast cancer, MUC-1 (CA27.29 triple-negative breast cancer, defined by lack of expres-
and CA15-3) and carcinoembryonic antigen[15,16]. sion of estrogen, progesterone and human epidermal
MUC-1 mucins belong to a protein family secreted growth factor receptor 2 (HER-2), heat shock protein 90
by the luminal surface of glandular epithelia. The up- has been identified as a critical target for its treatment[29].
regulation of MUC-1 mucin was detected in breast can- On the other hand, FKBP4 and S100A9 were suggested
cer patients, particularly in patients’ serum[17,18]. Family as putative prediction markers in discriminating doxo-
members of MUC-1-gene include MCA, BRMA CA549, rubicin and docetaxel drug sensitive patients from drug
CA27.29 and CA15-3. Among which, CA15-3 is reliable resistant patients[30], while Hsp27 was said to indicate
in indicating the clinical course of patients with meta- doxorubicin resistance[31]. The response of patients to
static cancer. The serum level of CA15-3 corresponds neoadjuvant paclitaxel/radiation treatment can be evalu-
to the tumor size. Although CA27.29 was found to be ated by the overexpression of alpha-defensins and mi-
more sensitive than CA15-3, it was less specific than crotubule associated protein 2 to indicate a pathological
CA15-3[19]. complete response. In addition, the presence of alpha-
Carcinoembryonic antigen (CEA) is a glycoprotein defensins and MAP2 were also used to indicate patients’
presence in the serum of cancer patients and can be de- sensitivity to taxane-based treatment[32].
tected using radioimmunoassay or enzyme-linked immu- Prognostic biomarkers provide information regarding
nosorbent assay[20]. CEA does not serve as a good indica- outcome irrespective of therapy. Amongst the potential
tor for metastatic breast cancer as the CEA serum level prognostic biomarkers for breast cancer are Ki-67 for a
was found elevated in only 15% to 68% of patients[21]. In primary tumor, cyclins, urokinase plasminogen activator,
addition, a high false-positive rate was detected among p53, p21, pro- and anti-apoptotic factors, BRCA1 and
the normal population, where a false positive rate rang- BRCA2[33-35].
ing from 10% to 27% was reported[20], limiting its clinical The discovery of the HER-2/neu oncogene has led
applications. The main clinical application of CEA is for to the formulation of an anti-cancer drug for patients
gastrointestinal cancers, specifically in colorectal malig- with breast cancer[36]. HER-2 belongs to the type I trans-
nancy. It is a very useful marker for the early detection membrane tyrosine kinase receptor family. HER-2 is
of liver metastasis in patients diagnosed with colorectal an important regulator for cell growth, differentiation
cancer[22]. during embryogenesis and for mammary development
Another potential serum based marker is CA­-125, a during puberty. Deregulation of HER-2 signaling in
useful serum marker for monitoring ovarian cancer and mammary cells promotes breast tumorigenesis[37]. Ap-
predicting the patient’s response to therapy. Neverthe- proximately 25% to 30% of human metastatic breast
less, CA-125 had insufficient sensitivity for diagnosis cancers over-expressed HER-2[38]. Overexpression of
of the disease[23]. In addition, serum CA-125 has been HER-2 is a significant predictor of reduced survival and
shown to be elevated in various forms of cancer, includ- shorter time to relapse[39,40]. This is because these tumors
ing ovarian, pancreatic, breast, colon, lung and endo- tend to grow faster and are more likely to metastasize
metrial carcinoma, making it less specific to any type of than tumors that do not overexpress HER-2. Thus,
cancer[24]. It is commonly agreed that CA-125 has a lack HER-2 has become an important therapeutic target for

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 Gam LH. Breast cancer and protein biomarkers

this subtype of breast cancer. When breast cancer is revealed 57 differentially expressed proteins between
diagnosed, HER-2 status is routinely assessed by either normal and cancerous tissues, including VDAC, transge-
immunohistochemical analysis for HER-2 expression or lin, Hsp 27, GRP78 and cathepsin. Following this study,
fluorescent in situ hybridization analysis for HER-2 gene Somiari et al[45] reported the identification of annexin Ⅴ,
copy[41]. Two HER-2-targeted therapies are approved by HSP 90, carbonic dehydrase, protein disulfide isomerase,
the United States FDA for treatment of HER2-overex- gelsolin and fibrinogen beta chain. Luo et al[53] added
pressing metastatic breast cancer, namely Trastuzumab to the list of differentially expressed proteins, includ-
(Herceptin) and Lapatinib (Tykerb). The presence of ing manganese SOD, biliverdin reductase B, carbonic
HER-2 overexpression is a predictive factor that may anhydrase Ⅰ and annexin Ⅰ, binding protein 4, cofilin
indicate successful use of trastuzumab (Herceptin)[40]. 1, profiling 1 and uracil DNA glycosylase. On the other
Trastuzumab (Herceptin) is a recombinant humanized hand, Deng et al[54] reported the potential of alpha-1-
monoclonal antibody targeted against the extracellular antitrypsin, EF-1-beta, cathepsin D, translationally con-
HER-2 receptor. The initial clinical trials of trastuzumab trolled tumour protein, SMT3A and PSMA1 as candi-
to be used as a sole agent in HER-2-overexpressing date biomarkers for patients with breast cancer. Besides
metastatic breast cancer demonstrated a response rate these studies, there are many recent reports on the iden-
ranging from 12% to 34% for a median duration of 9 tification of biomarkers in breast cancer[26-30]. Although
months[42]. the potential use of most reported biomarkers for breast
Early detection of breast cancer increases the sur- cancer has been scientifically proven, they need to be
vival rate of patients[43]. However, early symptoms of clinically validated.
breast cancer are sometimes absent or not recognized.
It is often detected in the advanced stage and is untreat-
able when the cancer is diagnosed[16]. Thus, a reliable HETEROGENEITY BETWEEN PATIENTS
biomarker is needed to rule out breast cancer in the early It is a challenge to identify a common biomarker that fits
state. Unfortunately, currently available tumor markers all patients. Many different factors are involved in the
lack the specificity and sensitivity to be used in early de- development of cancer. They include age, race, family
tection of breast cancer[13,16]. history, personal history of cancer, presence of viruses,
mutations in cell regulation genes and tumor suppressing
genes, exposure to carcinogens, lack of physical activity
PROTEOMIC APPROACH FOR and diet[55,56]. All these factors will cause heterogene-
BIOMARKER IDENTIFICATION ity in protein expression between patients. Therefore,
individualized medicine has become a popular trend for
Protein profiling studies on different types of cancer
treating cancer in Western countries. Nevertheless, in
have been carried out by researchers throughout the
developing countries, such a treatment will be too ex-
world. The 2D-PAGE coupled with mass spectrometry,
pensive for most patients. In the author’s laboratory, we
isotope coded affinity tags, multidimensional protein
have received surgically removed tissues from patients
identification technology, protein array technology and
with breast and colon cancer. In general, Malaysia is a
surface enhanced laser-desorption ionization-time of
country populated by three main ethnic groups, namely
flight are among the common technologies applied in
Malays, Chinese and Indian. Although the environment
proteomic study[44-46]. The proteome of a cell contains
and lifestyle factors are relatively similar between the eth-
all of the gene products that represent the functional
nic groups, they originated from different parts of the
output of the cell[47]. This makes proteomics a promising
world, with the Malays and Chinese mainly from China-
tool for characterizing cells and tissues of interest and
Mongolia regions and the Indians mainly from south In-
for biomarker discovery[48].
dia. We have shown in our studies[47] that the Malays and
It has been estimated that only 2% of human diseases
Chinese have relatively similar protein profiles, while In-
result from single gene defects. As for the remaining 98%
dians are very different. Therefore, the usability of each
of human diseases, epigenetic and environment factors
protein biomarker to be commonly used for a cancer per
need to be considered as they affect both etiology and
se among Malaysian patients was not reliable, but when
severity of the disease[49]. Therefore, cancer biomarker
an ethnic-specific biomarker was identified for each
discovery targeting protein expressions has become pop-
ethnic group, their significance greatly increased. Con-
ular as proteomic approaches characterize both modified
sequently, we have suggested the possibility of ethnic
and unmodified proteins involved in cancer progression.
specific drug-targeted therapy, which may be more af-
In recent years, the emerging sciences of genomics and
fordable to patients from developing or under developed
proteomics have revealed the identity of proteins that
countries where health insurance is not well established.
can potentially serve as cancer biomarkers. Unfortu-
nately, very few of these biomarkers are reliable clinically
for prognosis or diagnosis of the disease and even fewer CHALLENGES FOR IDENTIFICATION OF
have been validated and approved for clinical usage[50,51].
The proteomics of normal breast and cancerous tis- BIOMARKERS FOR CANCER
sue was first reported by Wulfkuhle et al[52]. The authors A few criteria are required for biomarkers to be effec-

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 Gam LH. Breast cancer and protein biomarkers

tively used in diagnosis, prognosis or treatment of can- to be tagged on a specific antibody that recognizes the
cer. First is the specificity of the biomarker to a type of biomarker on the cancer cell. In order to be used as a
cancer and such biomarker should be uniquely expressed biomarker in drug targeted therapy, the biomarker is best
in cancerous tissues only. Furthermore, consistent ex- to be uniquely expressed on the tumor surface at high
pression of the protein biomarker in cancer patients will abundant quantity for easy recognition and access of the
surely increase its reliability as an indicator of the dis- drugs. Although such biomarkers may not exist, there
ease. Moreover, the abundant expression of the protein are abundantly expressed common proteins on the tu-
biomarker will ease its detection or its recognition as a mor surface that are differentially expressed, where their
target for treatment. expression levels were found much higher in cancerous
In the author’s experience of researching the po- tissues than normal tissues. These differentially ex-
tential biomarkers for cancer, none of the proteins met pressed abundant proteins on the surface of cancerous
the criteria of biomarkers in terms of consistent and tissues may serve as a good target for recognition when
unique expression in all cancer patients. Instead, we have its abundance is much higher than that of the normal
detected many common proteins between normal and tissues.
cancerous tissues that were differentially expressed[57],
indicating that the similar types of cell activities were
operating between normal and cancerous cells while the POSSIBLE SOLUTION BY COLLECTIVE
rate of operation differs between the two tissues; cancer USE OF BIOMARKERS
cell activities repeat more frequently than normal cells,
The use of an individual protein as the sole biomarker
which causes a rapid cell growth that leads to tumor for-
for diagnosis, prognosis or treatment for cancer no
mation. There may be uniquely expressed protein in can-
doubt simplifies the procedure. However, it has been
cerous tissue but such proteins may express themselves
shown in many studies that protein expression variation
in low quantities, making them not a suitable biomarker
between patients is the main halting factor of the devel-
for drug-targeted therapy.
opment of devices as the cost of such development is
tremendously high; however, its usability is limited to a
CHALLENGES FOR IDENTIFICATION OF small group of patients. One of the possible solutions
is the collective use of biomarkers to achieve the desired
BIOMARKERS FOR DRUG-TARGETED goal. Through principle component analysis and linear
THERAPY IN CANCER TREATMENT discriminant analysis statistical analysis, we have shown
previously[58] that the collective use of biomarkers in can-
Currently, most of the drugs used in chemotherapy are cer has tremendously increased the correct identification
non-targeted, leading to two consequences. Firstly, the of cancerous tissues. The combined use of biomarkers
quantity of drug used in treatment was generally more has also been shown to give a better prognosis and in-
than that required to fight cancer because the drug will crease sensitivity and specificity to predict the response
be circulated in the body without a precise target, leading of patients to chemotherapeutic agents[33]. This will also
to the second consequence, the side-effects of the drug reduce the possibility of a false diagnosis as the reliabil-
on patients who undergo chemotherapy treatment. The ity of a group of biomarkers is better than the sole use
solution to this problem is drug-targeted therapy, where of a single biomarker.
the drug will be targeted at the side of tumor so that the
amount of drug used can be reduced and therefore the
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S- Editor Li JY L- Editor Roemmele A E- Editor Xiong L

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