Journal of Cancer Therapy, 2012, 3, 741-748
http://dx.doi.org/10.4236/jct.2012.325093 Published Online October 2012 (http://www.SciRP.org/journal/jct)
741
CAG and GGN Repeat Length Polymorphisms of
Androgen Receptor Gene in Women with Breast Cancer:
A Case-Control Study from South India
Durgadatta Tosh1, Bineet Panda1, Tipirisetti Nageswar Rao2, Arvind Babu1, Vishnupriya Satti2,
Digumarti Raghnadharao3, Lalji Singh1, Lakshmi Rao1*
1Centre for Cellular and Molecular Biology, Hyderabad, India; 2Department of Genetics, Osmania University, Hyderabad, India;
3Department of Medical Oncology, Nizams Institute of Medical Sciences, Hyderabad, India.
Email: *lakshmi@ccmb.res.in
Received April 17th, 2012; revised May 22th, 2012; accepted June 13th, 2012
ABSTRACT
Aim: The Androgen Receptor (AR) is a ligand-dependent transcriptional activator and the AR gene contains a highly
polymorphic trinucleotide repeat CAG and GGN in the first exon. Given the lack of information AR-CAG and GGN
repeat polymorphism and its potential correlation with breast cancer in South Indian women, we conducted a case-con-
trol study to observe the effects of CAG & GGN repeat length polymorphism and risk of breast cancer. Methods:
Polymorphisms for AR-CAG and GGN repeat length was detected by Gene Scan analysis in the genomic DNA from
cases with breast cancer and controls. Results: Association between AR genotype was calculated by categorising alleles
as short (S) and long (L) and taking median value as the cut-off. LL genotype of CAG repeat was found to be associated
with breast cancer (OR, 4.58; 95% CI, 10.61 - 1.98; p—0.0004). GGN repeat having 21 was found in most of the
cases and none of the cases showed 20 repeats thus indicate that alleles having homozygous repeat 20 may be protective
towards breast cancer. Also, SS genotype was observed in 56.84% of cases and in 73.03% of controls (OR, 0.48; 95%
CI, 0.26 - 0.89; p value, 0.02). Conclusion: Our results indicate that longer CAG and GGN repeat may be associated
with breast cancer whereas, the shorter GGN repeat length genotype of AR are protective.
Keywords: Breast Cancer; Androgen Receptor; CAG; GGN
1. Introduction
Breast cancer is the most common cancer and the leading
cause of the cancer deaths in women today. The inci-
dence of breast cancer varies greatly around the world: it
is lowest in less-developed countries, greatest in the
more-developed countries and is on the rise especially in
developing countries such as India. A recent data showed
that India has one of the highest cancer rates in the world
[1]. The incidence of breast cancer in India is on the rise
and is rapidly becoming the number one cancer in
women, pushing the cervical cancer to the second spot.
The aetiopathogenesis of breast cancer is largely un-
known, but most of the available evidences suggest that
it is a multifactorial disease [2]. Exposures to endoge-
nous and exogenous hormones are known to influence
breast cancer risk. Androgens, the predominant sex ster-
oid hormones in postmenopausal women, act through the
androgen receptor (AR), a member of the steroid receptor
subfamily. Among postmenopausal women, androgen lev-
els appear to be positively associated with breast cancer
risk [3], but it is not known whether AR has a role in the
mediation of these effects.
Androgen action is mediated at the transcriptional
level by the AR in breast cancer cells [4,5]. The AR and
androgens induce proteins, like prostate-specific antigen
(PSA) (98%) and the gross cystic disease fluid protein-15
(GCDFP-15) (92%), in the breast cancer specimens, con-
firming that AR is functionally active in human breast
cancer cells [6]. Also, the AR is found to be expressed in
>70% of breast cancers and has been implicated in breast
cancer pathogenesis [7-10]. However, the role of andro-
gens in breast cancer development and carcinogenesis
remains unclear [11,12].
The AR, which is genetically polymorphic, is codified
by the AR gene which is located on the X chromosome (q
11.2 - q 12). The AR gene spans 90 kb, contains eight
exons and encodes for a protein of about 917 amino acids
[13,14]. The exon 1 of AR gene contains two (microsa-
tellite) trinucleotide repeat polymorphisms, the CAG (en-
coding for polyglutamine) and the GGN (encoding for
*Corresponding author
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CAG and GGN Repeat Length Polymorphisms of Androgen Receptor Gene in Women with Breast Cancer:
A Case-Control Study from South India
742
polyglycine) repeat sequences. These polymorphisms
flank the N-terminal domain of AR protein, where the
transactivation activity of the protein resides [4].
Several studies have shown the effect of CAG poly-
morphism on the transactivation capacity of the receptor;
the longer the repeat the less efficient the transactivation
[15,16], which typically is in the range of 6-39 repeat
units. The role of (CAG)n polymorphism of AR in cancer
predisposition is supported by association studies of
breast and prostate cancer risk. Variation of the CAG-
AR length polymorphism shows remarkable differences
among diverse ethnic groups [17]. African populations
have the shortest CAG repeats, whereas the Asian popu-
lations possess the longest, while Caucasians and Ameri-
can Indians have medium number of repeat sequences
[18,19]. Hence, the predisposition of these populations to
BC is also known to vary accordingly.
The polyglycine tract in the AR protein is encoded by
(CGT)3 GGG (GGT)2 (GGC)n, an invariant six-glycine
tract (GGT/GGG) followed by a polymorphic GGC re-
peat, that is less polymorphic than CAG repeat [14-20].
About 90% of normal AR contains 16-18 CGG repeats.
Most of the experimental studies conducted so far re-
port on the effects of lengthening either of the CAG or
the GGN repeats, while the other repeat is maintained as
a constant. However, recent observations on diverse hu-
man tumors [21,22] suggest that combination of different
repeat length in the normal range could increase the risk
of developing cancer [6]. Hence, it remains to be deter-
mined whether the combined effects of CAG and GGN
repeat polymorphism on androgen action are independent
or not. Till date, data supporting the relationship between
AR polymorphism and BC came exclusively from Amer-
ica and European countries. Though there are a few re-
ports from Asia on AR polymorphism in BC, there is no
data been reported from South India. Therefore, we con-
ducted a case-control study to observe the effects of
CAG & GGN repeat length polymorphism and risk of
BC, which could ultimately prove to be useful for the
early prognosis of the high risk patients and further
management of such individuals.
2. Materials and Methods
2.1. Patient and Control Recruitment
Ninety-six women with breast cancer of age group 25 -
79 years were recruited from Department of Medical
Oncology, Nizams Institute of Medical Sciences, Hy-
derabad, India. All the patients were assessed clinically,
with complete medical history. Respective consent forms
from the patients recruited for the study were collected
by the concerned clinic. And eighty nine controls of age
group 30 - 70 years were randomly selected from the
healthy women of general population with no familial
history of breast cancer. Recruitment of the controls was
entirely ethnically population-based to support the study.
The Institutional Review Board of Centre for Cellular
and Molecular Biology (CCMB), Hyderabad, approved
the study.
2.2. DNA Extraction
A 5-ml aliquot of peripheral blood was collected in
EDTA vacutainers for genomic DNA isolation. DNA was
extracted using the Nucleon BACC2 DNA extraction kit
(Amersham Pharmacia Biotech, Piscataway, NJ, USA)
according to the manufacturer’s protocol.
2.3. Molecular Analysis and Assessment of the
CAG and GGN Repeats
The CAG repeat region of the AR gene was amplified
with a pair of primers, forward:
5’FAM-TCCGAATCTGTTCCAGAGCGTGC-3’, reverse:
5’-GCTGTGAAGGTTGCTGTTCCTC-3’ flanking the re-
peat region. PCR reaction mixture consisted of 1.0 µl
PCR buffer (10X), 1.0 µl MgCl2 (25mM), 1.0 µl dNTPs
(10mM), 1.0 pM of each primer, 0.5 units AmpliTaq
GoldTM DNA polymerase and 20 ng genomic DNA. PCR
was done under the following conditions; initial denatu-
ration at 94˚C for 12 minutes followed by 30 cycles of
94˚C for 1 minute, 60.5˚C for 1 minute and 72˚C for 1
minute with a final extension at 72˚C for 30 minutes. GGN
repeat was amplified with a pair of primers: forward
5’FAM-CCGCTTCCTCATCCTGGCACAC 3’ and re-
verse 5’GCCGCCAGGGTACCACACATC 3’ flanking
the repeat region. PCR reaction mixture included 1.0 µl
PCR buffer (10×), 1.0 µl MgCl (25 mM), 1.0 µl dNTPs
(10 mM), 1.0 µl DMSO (100%), 1.0 µl glycerol (100%),
1.0 pM of each primer, 0.5 units Amplitaq Gold DNA
polymerase and 20 ng genomic DNA. PCR conditions
consisted of denaturation at 96˚C for 15 minutes, fol-
lowed by 40 cycles of 96˚C for 1.5 minutes, 55.5˚C for 1
minute and 72˚C for 3 minutes and a final extension at
72˚C for 20 minutes. For GeneScan, 3.0 µl of PCR
product was mixed with 0.2 µl of LIZ500 and 6.8 µl
Hi-Di formamide. Upon denaturation for 5 minutes at
96˚C and cooling for 5 minutes on ice, samples were run
on 3730 DNA analyzer (Applied Biosystems, USA). PCR
and genotyping were repeated for all samples to confirm
the number of repeats. The raw data was further analyzed
using GeneMapper software (Applied Biosystems, USA).
2.4. Statistical Analysis of Results
Each variable was summarized according to its scale and
distribution. The genescan results were analyzed on Gene-
Copyright © 2012 SciRes. JCT
CAG and GGN Repeat Length Polymorphisms of Androgen Receptor Gene in Women with Breast Cancer:
A Case-Control Study from South India
Copyright © 2012 SciRes. JCT
743
However, the mean variation in the CAG repeat be-
tween cases (mean = 20.13) and control (mean = 19.8)
was found to be statistically non significant (p value—
0.83).
Mapper 3.1 software to check for CAG and GGN length
variations. Statistical significance is reached in all tests
when a two tailed p < 0.05 was obtained. Main analyses
were carried out using the SPSS version 16.0 statistical
package from SPSS Inc., Chicago, IL, USA. The GGN repeat ranged from 10 to 25 repeats where
no allele was found to have 11 or 14 repeats. The AR
allele with 21 GGN repeats was predominant in all cases
with a very low frequency of smaller allele distributed
between the ranges of 10 to 25. While AR allele with 20
GGN repeats was predominant in all the control samples,
no case having AR allele with 20 GGN repeat was found
(Figure 2). AR allele with 21 repeats was found in
68.94% of the cases whereas, in controls, allele with 20
repeats had the highest frequency of 75.84% and the rest
of the alleles were distributed scarcely among the range
of 10 to 25. Apart from this no allele with repeat size of
11, 13, 14 and 16 were found in any control sample.
3. Results
Gene Scan was done for the two-microsatellite regions of
AR gene i.e. CAG and GGN repeats in all the cases and
controls.
3.1. Gene Scan Results
In the present study, we have analyzed the association of
two polymorphic repeats namely CAG and GGN of the
AR gene located in the coding region of the exon 1.
3.2. Distribution of CAG and GGN Alleles in
Cases and Controls On comparing homozygous repeat of GGN in cases
and controls, it was observed that in controls 20 repeat is
predominant (96.30%) whereas, in cases 21 repeat was
found to be predominant (90.00%) (Table 1).
The frequency distribution of both CAG and GGN repeat
alleles in the present study is shown in the table.
The assayed case and control population showed 18
different CAG repeats, ranging from 11 to 28. Alleles
with 11, 12, 26 repeats were not present in any of the
cases and among all the controls, alleles with 13, 14, 27
repeats were not present. Among all cases, repeat 19 was
observed with highest frequency of 13.54%, while in
controls, allele with 20 repeats had the highest frequency
of 25.28%. The CAG allelic distribution was near normal
(Figure 1).
3.3. CAG and GGN Polymorphism and Breast
Cancer
The number of CAG repeats has been proposed to be
related to the activity of the receptor, hence we divided
the subjects into three subgroups, SS (small small), SL
(small long) and LL (long long) genotype by using me-
dian value as the cut-off according to the strategy fol-
lowed by the other reports [21,23,24]. For CAG repeat
Figure 1. Distribution of CAG repeats of AR gene in women with breast cancer.
CAG and GGN Repeat Length Polymorphisms of Androgen Receptor Gene in Women with Breast Cancer:
A Case-Control Study from South India
744
Figure 2. Distribution of GGN repeats of AR gene in women with br east cancer.
Table 1. Comparison of frequencies of CAG and GGN homozygous repeats in cases and controls.
REPEATS CAG GGN
Controls Cases Controls Cases
Homozygous
n % n % n % n %
13-13 - - 0 1 2.00
14-14 - 1 4.76 - -
15-15 1 8.33 0 0.00 - -
17-17 0 0.00 3 14.29 - -
18-18 1 8.33 2 9.52 - -
19-19 2 16.67 5 23.81 - -
20-20 4 33.33 4 19.05 52 96.30 0 0.00
21-21 2 16.67 3 14.29 1 1.85 45 90.00
22-22 1 8.33 3 14.29 0 0.00 4 8.00
23-23 - - 1 1.85 0 0.00
26-26 1 8.33 - - -
Total 12 13.48 21 21.87 54 60.67 50 52.63
n 89 96 89
the median was taken to be 19 repeats (Mean ± SD 19.13
± 2.76) for cases and 20 repeats (Mean ± SD 19.40 ±
2.72) for controls. In cases CAG allele 19 was consid-
ered to be a Short (S) allele and allele 20 was consid-
ered as a Long (L) allele and in control samples, CAG
allele 20 was considered to be a Short (S) allele and
allele 21 was considered as a Long (L) allele. Analysis
revealed that 35.42% of cases and 49.44% of the controls
had SS genotype. 36.46% of cases and 42.7% of the con-
trol samples were of SL genotype, whereas, very few LL
genotype were present in controls (7.86%) compared with
case samples of 28.12% (OR, 4.58; 95% CI, 10.61 - 1.98)
(Figure 3).
For GGN repeat the median was 21 repeats (Mean ±
SD 21.00 ± 1.56) for cases and 20 repeats (Mean ± SD
19.87 ± 1.45) for controls. In case samples the GGN re-
peat allele having 21 repeats was taken to be a Short (S)
allele and allele 22 repeats was considered to be a Long
(L) allele and in control samples, GGN repeat allele hav-
ing 20 repeats was taken to be a Short (S) allele and
allele 21 repeats was considered to be a Long (L) allele.
Analysis revealed that 56.84% of cases and 73.03% of
Copyright © 2012 SciRes. JCT
CAG and GGN Repeat Length Polymorphisms of Androgen Receptor Gene in Women with Breast Cancer:
A Case-Control Study from South India
745
the controls had a SS genotype. 38.95% of cases and
24.72% of the control samples were of SL genotype,
while LL genotype showed a very scarce distribution
(Figure 4).
4. Discussion
We have investigated a potential link between the CAG
and GGN short tandem repeats of the AR gene in breast
cancer in the South Indian women. The allelic frequen-
cies of CAG in our control samples resemble those re-
ported for Caucasian and Japanese populations [5,25,26].
In case of GGN repeat, alleles with 20, 21 and 22 repeats
were found most frequently in our study.
In CAG repeat, alleles with 20 repeats were observed
in 13.02% of patients and 25.28% of controls (OR, 0.44;
95% CI, 0.26 - 0.75) which shows a significant correla-
tion between case and control samples (p-value, 0.002).
Taking median as the cut-off we have categorised
CAG allele into 2 types: S (short) and L (long), and
hence the possible genotypes are—SS (Short-Short), SL
(Short-Long) and LL (Long-Long). SS and SL genotypes
do not show any significant correlation with respect to
their p value, whereas, the p value of LL genotype (0.0004)
was highly significant (OR, 4.58; 95% CI, 10.61 - 1.98).
This clearly indicates that long CAG alleles are highly
associated with BC.
Figure 3. Frequency (%) of CAG repeats in case-control and their subgroups having the SS (short/short), SL (short/long) or
LL (long/long) alleles.
Figure 4. Frequency (%) of GGN repeats in case-control and their subgroups having the SS (short/short), SL (short/long) or
LL (long/long) alleles.
Copyright © 2012 SciRes. JCT
CAG and GGN Repeat Length Polymorphisms of Androgen Receptor Gene in Women with Breast Cancer:
A Case-Control Study from South India
746
In our study, controls showed a very high frequency of
GGN alleles having 20 repeats (96.3%), whereas, in case
samples, 21 (90%) and 22 (8%) repeats had very high
frequencies. Having categorised GGN genotypes into
three, i.e. SS, SL and LL, it was observed that SS geno-
type was observed in 56.84% of cases and in 73.03% of
controls (OR, 0.48; 95% CI, 0.26 - 0.89; p value, 0.02).
Our result shows that 20 homozygous repeats are protec-
tive whereas 21 homozygous repeat is affective in caus-
ing breast cancer. It is difficult to say if this one or two
repeat shift can be a plausible risk factor or not. It re-
quires a large population study to validate. But in our
study none of the cases showed 20 repeats which clearly
indicate that alleles having homozygous repeat 20 may
be protective towards breast cancer in south Indian
women.
Several case-control studies have investigated the rela-
tionship between CAG repeat length in the AR and breast
cancer risk but till date there have been only a few stud-
ies which have taken both CAG and GGN repeat length
into consideration. A population based study of young
women from USA found larger CAG repeat (43) to
increase the risk of breast cancer, whereas women with
long GGN alleles and those with a 33 cumulative repeat
size had a decreased risk of breast cancer [27]. A recent
case-control study from Spain population showed CAG
repeat 22 and GGN 24 to be associated with in-
creased risk of breast cancer [5].
Our result in CAG repeat showed that patient having
20 repeat number and LL genotypes may have a risk of
getting breast cancer. And GGN repeat 21 showed a
high risk of getting breast cancer. Our study is in accord
with the previous two studies with respect to the CAG
repeat, whereas, our result found no evidence to support
the above mentioned study from USA in the case of
GGN repeats which had described long GGN repeats to
be protective [27].
The magnitude of the increased risk we observed with
the (CAG)n genotype was broadly similar to the findings
of the population based study of breast cancer in USA
and Spain, whereas it showed contradictory results with
the data published by YouJin Hao et al. where they ana-
lyzed seven detailed genotyping case-control studies and
found that a long CAG sequence has a protective effect
on breast cancer [28].
Our results suggest that breast cancer risk might be
likely related to androgenic activity, and longer CAG and
GGN repeat may be associated with disease whereas, the
shorter GGN repeat length genotype of AR are protective.
We observed a stronger and more consistent association
between GGN repeat polymorphisms of the AR gene and
breast cancer.
Androgens are known to increase the risk of breast
cancer by either acting as estrogen precursors or by direct
action on breast cancer cells by binding to AR. Andro-
gens have also been reported to act as antiproliferative
agents in the presence of estrogens in some breast cancer
cell lines. Both these effects of androgens are expressed
through its binding to the AR [6]. Hence, the effects of
androgens are regulated by the androgen receptor. There-
fore, any polymorphism, like that of the CAG and GGN
tracts, might result in a variation in the AR activity.
Presence of long (L) CAG allele reduces the transcrip-
tional activity of the AR. Tertiary structure of AR poly-
glutamine repeats has not been characterized [6]. Repeat
length probably modifies the conformation of the protein
affecting either the homodimer structure, which is re-
quired for the active form of AR, or the recognition and
binding capability of AR homodimer to the Hormone
responsive elements (HREs). Hence affecting the tran-
scription of the genes that are androgen dependent and
therefore increasing the BC risk.
Similarly, the amount of the AR protein is important.
Because, the transcription machinery requires the con-
tinuous presence of androgen and androgen receptor and
therefore the homodimers they form for the production of
co-activators of transcription. Every time the gene is ex-
pressed, the transactivators (co-activators) are degraded
by a ubiquitin pathway [29], that is, transcription is a
cyclic process. Presence of long (L) GGN allele reduces
the AR protein yield. And, if the AR protein yield is low,
transcription machinery is again affected, increasing the
risk of breast cancer.
Though it has to be ascertained whether the effects of
CAG and GGN repeats on androgen action are inde-
pendent or not, certainly the risk of BC increases if both
together show any variation in repeat length since the
presence of both long CAG and long GGN will result in
both low levels of AR and low transcriptional activity,
multiplying the risk of BC.
Also, the SS genotype has been observed in aggressive
forms of cancer [30]. This further goes to show that the
androgens and hence the AR play a dual role—of pro-
tecting against cancer and also being one of the causes of
cancer. Hence, there seems to be a balance between the
dual roles of the androgen and its receptor, which in a
way seems to be related to the repeat lengths of CAG and
GGN tracts.
5. Conclusion
This is the first study addressing the association of CAG
and GGN repeat length polymorphism in AR gene in
breast cancer in South Indian population. This finding
may help explain the higher rate of breast cancer among
South Indians, as well as their tendency to be diagnosed
with more extensive disease risk. Our results showed a
Copyright © 2012 SciRes. JCT
CAG and GGN Repeat Length Polymorphisms of Androgen Receptor Gene in Women with Breast Cancer:
A Case-Control Study from South India
747
strong correlation between CAG and GGN repeat poly-
morphism and breast cancer. It requires a further study
with a large population and different ethnic groups for
the early prognosis of high risk patients of various ethnic
populations and their respective management.
6. Acknowledgements
We are thankful to SVM, USA, for critically going
through the manuscript. The financial assistance from
Council of Scientific and Industrial Research, New Delhi,
Government of India, is greatly acknowledged.
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