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Reduction in breast cancer susceptibility due to XbaI gene polymorphism of alpha estrogen receptor gene in Jordanians

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Breast Cancer: Targets and Therapy
Authors:
Manar Atoum at Hashemite University
Manar Atoum
Foad Alzoughool at Hashemite University
Foad Alzoughool
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Abstract and Figures

Breast cancer is a global health concern among women worldwide. Estrogen receptor alpha (ERα) mediates diverse polymorphic effects in breast tissues that may relate to breast cancer susceptibility. The aim of this study was to evaluate the effect of −397 PvuII (T/C) and −351 XbaI (A/G) restriction fragment length polymorphism within intron 1 of ERα, and its effect on breast cancer susceptibility. A total of 156 women who were histopathologically diagnosed with breast cancer and 142 healthy Jordanian women were enrolled in this case–control study. Genomic DNA was extracted from whole peripheral blood, and the desired fragment was amplified using polymerase chain reaction followed by restriction digestion with PvuII and XbaI restriction enzymes. The results showed no significant association between PvuII polymorphism and breast cancer risk. However, a significant association was found between XbaI polymorphism and reduction in breast cancer risk within the “x” allele of heterozygotes (odds ratio [OR] 0.199, 95% confidence interval [CI] 0.09–0.044) and heterozygotes (OR 0.208, 95% CI 0.09–0.047). The combined analysis of PvuII and XbaI polymorphisms revealed a synergistic effect of Pp/Xx and pp/xx genotypes and a significant reduction in breast cancer risk with these genotypes. The results also showed no statistical differences among PvuII or XbaI polymorphisms based on stage, ER, progesterone receptor and expression of hormone receptor such as human epidermal growth factor receptor 2. This case–control study showed that XbaI polymorphism of alpha estrogen gene modified and reduced breast cancer susceptibility among Jordanians.
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Breast Cancer - Targets and Therapy 2017:9 45–49
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ORIGINAL RESEARCH
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/BCTT.S125652
Reduction in breast cancer susceptibility due
to XbaI gene polymorphism of alpha estrogen
receptor gene in Jordanians
Manar Fayiz Atoum
Foad Alzoughool
Department of Medical Laboratory
Sciences, Faculty of Allied Health,
Hashemite University, Zarqa, Jordan
Abstract: Breast cancer is a global health concern among women worldwide. Estrogen recep-
tor alpha (ERα) mediates diverse polymorphic effects in breast tissues that may relate to breast
cancer susceptibility. The aim of this study was to evaluate the effect of −397 PvuII (T/C) and
−351 XbaI (A/G) restriction fragment length polymorphism within intron 1 of ERα, and its
effect on breast cancer susceptibility. A total of 156 women who were histopathologically diag-
nosed with breast cancer and 142 healthy Jordanian women were enrolled in this case–control
study. Genomic DNA was extracted from whole peripheral blood, and the desired fragment was
amplified using polymerase chain reaction followed by restriction digestion with PvuII and XbaI
restriction enzymes. The results showed no significant association between PvuII polymorphism
and breast cancer risk. However, a significant association was found between XbaI polymorphism
and reduction in breast cancer risk within the “x” allele of heterozygotes (odds ratio [OR] 0.199,
95% confidence interval [CI] 0.09–0.044) and heterozygotes (OR 0.208, 95% CI 0.09–0.047).
The combined analysis of PvuII and XbaI polymorphisms revealed a synergistic effect of Pp/
Xx and pp/xx genotypes and a significant reduction in breast cancer risk with these genotypes.
The results also showed no statistical differences among PvuII or XbaI polymorphisms based on
stage, ER, progesterone receptor and expression of hormone receptor such as human epidermal
growth factor receptor 2. This case–control study showed that XbaI polymorphism of alpha
estrogen gene modified and reduced breast cancer susceptibility among Jordanians.
Keywords: breast cancer, gene polymorphism, XbaI
Introduction
Breast cancer is a serious life-threatening condition affecting women worldwide.1 It
ranks second among various causes of cancer death in women.2 In Jordan, 42.9% of
cancers diagnosed in women are breast cancers.3 Understanding the pathogenesis of
breast cancer is important in the innovative therapies for breast cancer diagnosis and
treatment. One of the most important risks of breast cancer is endogenous hormone
level. The genes of estrogen receptor (ER) pathway may influence breast cancer risk by
two possible mechanisms: 1) ER-mediated stimulation of breast cell proliferation with
a concomitant enhanced rate of mutations and 2) metabolism of estradiol to genotoxic
metabolites with a resulting increase in DNA mutations.4
Estrogen is a steroid hormone that is essential for the development of female
secondary sexual characters.4 Under normal conditions, it affects the growth, differen-
tiation and function of breast,5 uterus, vagina, ovary, testis, epididymis and prostate.6
However, under abnormal conditions, exposure to estrogen predisposes females to a
risk of developing breast cancer. Current hormonal therapies have benefited breast
Correspondence: Manar Fayiz Atoum
Department of Medical Laboratory
Sciences, Faculty of Allied Health,
Hashemite University, Zarqa 13115, Jordan
Tel +962 79 973 3894
Email manar@hu.edu.jo
Journal name: Breast Cancer - Targets and Therapy
Article Designation: Original Research
Year: 2017
Volume: 9
Running head verso: Atoum and Alzoughool
Running head recto: XbaI gene polymorphism in breast cancer reduction
DOI: http://dx.doi.org/10.2147/BCTT.S125652
This article was published in the following Dove Press journal:
Breast Cancer - Targets and Therapy
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Atoum and Alzoughool
cancer patients. However, their success is often limited to
patients whose tumors express ERα, but entirely ineffective
in ER-negative breast cancers.7
ERs are of special interest as their expression is always
affected in malignant cancer cells.8 ERs are nuclear recep-
tor proteins that have an estrogen-binding domain and a
DNA-binding domain.9 There are two types of ERs: 1)
ERα that is localized on 6q25.1 and associated with breast
cancer and 2) ERβ that is located on chromosome 14q22-
24 and functions as a tumor suppressor.10 Polymorphisms
in the ER genes may determine the biosynthetic activity of
circulating estrogen.
Nearly over half of all types of breast cancers overex-
press ERα and ~70% of these respond to anti-estrogen.11
Elevated levels of ERα in benign breast epithelium indicate
an increased risk of breast cancer.12 ERα status is essential in
making decisions about endocrine therapy with anti-estrogen
since ERα (+) status correlates with improved prognosis and
better overall survival.9
ERα is regarded as one of the significant prognostic
factors for breast, ovarian and lung cancers,13 miscarriage
and endometriosis. Single nucleotide polymorphisms were
associated with increased risk of cancers.14 The most char-
acterized single nucleotide polymorphisms of ERα located
in the first intron are the c454-397T>C- and c454-351A>G-
site polymorphisms. These polymorphisms are 397 and 351
base pairs upstream of exon 2 and are detected by restriction
enzymes PvuII or XbaI, respectively.15 These polymorphisms
were correlated with breast cancer incidence.16 PvuII altered
protein expression by interfering with ERα mRNA splicing,
but the mechanism of action of XbaI is still unknown.
Genetic studies on cancer are scarce in Jordan and only
few studies have screened gene polymorphism in breast
cancer.17–20 To our knowledge, no studies have determined
the role of ERα PvuII and XbaI polymorphisms in breast
cancer susceptibility among Jordanians. Therefore, the aim
of this study was to determine the frequency of ERα PvuII
and XbaI genotypes and the possible involvement of these
polymorphisms in breast cancer susceptibility among Jorda-
nian women with breast cancer.
Materials and methods
This study enrolled 156 women who were histologically and
clinically diagnosed with breast cancer and 142 age-matched
controls with no previous family history of any cancer from
Al-Basheer Hospital (2013–2015). International review
board approval was obtained from the Hashemite University
international review board committee and signed consent
forms were obtained from all patients. All clinical samples
were staged according to Atoum et al.21
Genomic DNA was extracted from all blood samples
using Wizard extraction kit (Promega, Madison, WI, USA)
and was stored at −80°C. Polymerase chain reaction was
carried out to amplify intron 1–exon 2 region of ERα gene
in three steps with annealing at 60°C in a thermal cycler
(Bio-Rad, Munich, Germany) in 25 μL reaction volume.
Each reaction mixture contained 10 pmol of each primer,
3 mM of MgCl2, 100 nM of each deoxynucleotide tri-
phosphate, 1 unit of Taq DNA polymerase and 100 ng of
genomic DNA. Primer sequences are as follows: forward
primer: 5′ AGG GTT ATG TGG CAA TGA CG 3′; reverse
primer: 5′ CCT GCA CCA GAA TAT GTT ACC T 3′. The
amplified fragment of 1374 base pairs was then digested
with PvuII and XbaI. The presence of PvuII restriction
site on both alleles (pp) was identified by two fragments
(850, 450), while the presence of XbaI on both alleles
(xx) was identified by two fragments (900, 400). Digested
fragments were then electrophoresed on 1.5% agarose gel
with ethidium bromide.
Statistical analysis
Statistical analysis was carried out using SPSS software. The
distribution of genotypes in cancer patients and controls was
evaluated by the Chi-square test. Odds ratio (OR) and 95%
confidence interval (CI) were used to estimate the relative
risk. A p-value <0.05 was considered statistically significant.
Results
Genotypic distribution of ERα PvuII and XbaI is shown in
Table 1. With reference to PP genotype, no significant asso-
ciations were found between the variations of breast cancer
risk and P alleles in homozygotes or heterozygotes. There was
no statistical difference in the prevalence of P allele between
Table 1 Frequency of estrogen receptor alpha polymorphism
PvuII and XbaI among breast cancer patients and controls
Genotype Cases
n=156, n (%)
Controls
n=142, n (%)
OR 95% CI p-value
PP 24 (15.4) 19 (13.4) 1 NA NA
Pp/pp 132 (84.6) 123 (86.6) 1.18 0.61–2.25 0.62
Pp 87 (55.8) 82 (57.7) 1.19 0.61–2.33 0.61
pp 45 (28.8) 41 (28.9) 1.15 0.55–2.40 0.71
XX 39 (25) 9 (6.3) 1 NA NA
Xx/xx 117 (75) 133 (93.7) 0.203 0.09–0.43 0.0001
Xx 71 (45.5) 82 (57.7) 0.199 0.09–0.44 0.0001
xx 46 (29.5) 51 (35.9) 0.208 0.09–0.47 0.0002
Note: Signicant p-value <0.05.
Abbreviations: CI, condence interval; OR, odds ratio; NA, not available.
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XbaI gene polymorphism in breast cancer reduction
cases (84.6%) and controls (86.6%). Nearly 15.4% of the
patients and 13.4% of the controls were homozygous for P
allele. About 55.8% of the patients and 57.7% of the controls
were heterozygous for this allele. No significant association
was found between breast cancer risk and P allele in het-
erozygotes (OR 1.19, 95% CI 0.61–2.33) or homozygotes
(OR 1.15, 95% CI 0.55–2.40). A statistical difference was
observed in the prevalence of X allele between cases (75%)
and controls (93.7%). XbaI polymorphism in x allele was
more prevalent among controls (35.9%) compared to patients
with breast cancer (29.5%), (OR 0.208, 95% CI 0.09–0.47).
Combined analysis of PvuII and XbaI genotypes revealed
a synergistic effect of Pp/Xx (OR 0.11, 95% CI 1.19–9.66,
p = 0.03) and pp/xx (OR 0.11, 95% CI 0.02–0.58, p = 0.01)
as carriers of these genotypes showed reduced risk of breast
cancer (Table 2).
Table 3 shows the histological subtypes of different PvuII
and XbaI genotypes among women with breast cancer. No
statistical difference was found within either PvuII or XbaI
genotypes (p = 0.83, 0.81, respectively) among different
breast cancer stages.
No statistical differences were found among PvuII or
XbaI polymorphisms based on ER, progesterone receptor and
expression of hormone receptor such as human epidermal
growth factor receptor 2 (HER2) (Table 4).
Discussion
This case–control study was conducted to analyze the asso-
ciation between PvuII and XbaI polymorphisms and breast
cancer risk among Jordanian females. No association between
the variation of breast cancer risk and pp genotype was found
Table 2 Breast cancer risk in relation to PvuII and XbaI
combination genotypes
Genotype Cases Control OR 95% CI p-value
PP/XX 8 2 1 NA NA
PP/Xx 10 8 0.31 0.05–1.90 0.20
PP/xx 6 14 0.107 0.01–0.66 0.16
Pp/XX 23 4 0.70 1.19–29.66 0.70
Pp/Xx 35 52 0.11 1.19–9.66 0.03
Pp/xx 29 31 0.28 0.04–1.19 0.08
pp/XX 8 3 0.67 0.08–5.12 0.69
pp/Xx 26 2 3.25 0.39–26.91 0.27
pp/xx 11 26 0.11 0.02–0.58 0.01
Note: Signicant p-value <0.05.
Abbreviations: CI, condence interval; OR, odds ratio; NA, not available.
Table 3 Breast cancer patient stages among PvuII and XbaI
genotypes
p-valueTotalStage IVStage IIIStage IIStage ICancer
genotype
0.832451171PP
872935221Pp
451121121pp
0.8139919110XX
711237202Xx
46923140xx
Note: Signicant p-value <0.05.
Table 4 Estrogen receptor, progesterone receptor and hormone
receptor HER2 among breast cancer cases
p-valueHER2
positive
PR positiveER positiveCancer
genotype
0.1991713PP
115148Pp
132821pp
339682Total
0.4371511XX
125053Xx
102623xx
299187Total
Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HER2, human
epidermal growth factor receptor 2.
105
100
95
90
Survival (%)
85
80
246810 12
Months
xx genotype Non-xx genotype
14 16 18 20 22 24
Figure 1 Kaplan–Meier survival plot showing differences in survival probability among xx breast cancer genotype compared to non-xx genotype.
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Atoum and Alzoughool
compared to PP genotype, but a significant association was
found between reduced breast cancer risk and xx genotype
compared to XX genotype. Also no association was found
between the variation of breast cancer risk and PvuII or XbaI
genotypes based on breast cancer stages, presence of ER,
progesterone receptor and expression of hormone receptor
HER2 among breast cancer females. The results of this study
are in contrast with those of a Chinese study that analyzed
PvuII and XbaI for breast cancer risk. A significant associa-
tion was found between Pp and pp genotypes and increased
breast cancer risk, whereas no significant association was
found between Xx and xx genotypes and increased breast
cancer risk.22 The results of this study are also in contrast
with the results of another Chinese study that was conducted
among another Chinese group23; the results showed no effect
of PvuII and XbaI polymorphisms on breast cancer risk.
This study showed a significant association between reduced
breast cancer risk and xx genotype, in contrast to the results
of a study on Pakistani breast cancer patients,24 and similar
to the results of a study on Portuguese population where xx
genotype was associated with decreased breast cancer risk.16
This contradiction may be due to the large and different
biological processes where alpha estrogens and their recep-
tors are involved. The possible mechanisms by which PvuII
and XbaI polymorphisms affect breast cancer are still not
known. The position of PvuII and XbaI polymorphisms in the
intron near the promoter may contain regulatory sequences
like enhancers that affect the expression of alpha receptor
gene. Intronic enhancers act as regulatory sequences that
control transcriptional regulation.25 Nowadays, ERα has been
signaled as a possible marker for many diseases, including
different cancers and immunological diseases.
Conclusion
The results of this case–control study showed a significant
reduction in breast cancer risk in women carrying xx geno-
type. So further studies are needed with larger sample size
among different populations to clarify how ERα and XbaI
may modify an individual’s susceptibility to breast cancer
risk.
Acknowledgment
We acknowledge the Hashemite University for the financial
support to this project and the workers at Al-Basher Hospitals
for their help in sample collection.
Disclosure
The authors report no conflicts of interest in this work.
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... [13] Although the association between ERa gene Pvu II polymorphism and breast cancer susceptibility has been extensively reported currently, there are great differences among study conclusions. Atoum et al [14] did not found any correlation between ERa gene Pvu II polymorphism and breast cancer risk in Jordaneses, but some investigators discovered that there was a significant correlation between ERa gene Pvu II polymorphism and breast cancer risk in Brazilians and Northern Indians and patients with p allele had lower morbidity of breast cancer. [15,16] Although meta-analysis have been conducted in pre-studies, [13,[17][18][19] there are still new literatures on the association between ERa gene Pvu II polymorphism and breast cancer risk published. ...
... Atoum and Alzoughool [14] 2017 Jordanians Caucasian HB TaqMan 156/142 Y 6 Sun et al [20] 2015 China Asians HB MassARRAY IPLEX platform 481/463 Y 5 Madeira et al [15] 2014 Brazil Caucasian HB PCR-RFLP 64/72 Y 5 Chattopadhyay et al [16] 2014 India Caucasian PB PCR-RFLP 360/360 Y 6 Cao * et al [21] 2014 China Asians HB PCR-RFLP 221/252 Y 5 Tang et al [12] 2013 China Asians HB MALDI-TOF 794/845 Y 6 Lu and Xu [13] 2013 China Asians PB PCR-RFLP 542/1016 Y 8 Ramalhinho et al [22] 2013 Portuguese Caucasian HB PCR-RFLP 107/121 Y 6 Han et al [23] 2011 China Asians PB TaqMan 859/877 Y 7 Sakoda et al [24] 2011 China Asians PB SNaPshot assays 612/874 Y 7 Deng * and Lu [25] [27] 2009 UK Caucasian PB PCR-RFLP 4362/4548 Y 5 Sonestedt et al [28] 2009 Sweden Caucasian PB SEQUENOM 539/1073 Y 6 González-Mancha et al [29] 2008 Spain Caucasian PB PCR-RFLP 444/704 Y 5 Ladd et al [30] 2008 Netherlands Caucasian PB NA 190/3703 Y 5 Hu et al [31] 2007 China Asians HB PCR-RFLP 113/113 Y 5 Wang et al [32] 2007 USA Caucasian PB PCR-MPLA 392/783 Y 5 Kjaergaard et al [33] 2007 Denmark Caucasian HB TaqMan 1256/2489 Y 5 Surekha et al [34] 2007 India Caucasian HB TaqMan 249/248 Y 6 Shen et al [35] 2006 China Asians PB PCR-RFLP 247/274 Y 5 Modugno et al [36] 2005 USA Caucasian PB PCR-RFLP 248/3901 N 5 Onland-Moret et al [37] 2005 Netherlands Caucasian PB PCR-RFLP 308/337 Y 4 Lu * et al [38] 2005 China Asians HB PCR-RFLP 138/140 Y 5 Wedrén et al [39] 2004 Sweden Caucasian PB PCR-RFLP 1292/1418 Y 7 Cai et al [40] 2003 At present, genetic polymorphism has become one of the hot topics in the studies on risk factors of breast cancer. Although the association between ERa gene PvuII polymorphism and breast cancer risk has been reported widely, the conclusions vary in different studies due to the difference of study design, study methods, regions and ethnicities, etc. ...
... Some researchers believed that there was no association between ERa gene PvuII polymorphism and breast cancer risk. [14,20] Therefore, this study mainly analyzed 26 studies on the association between ERa gene Pvu II polymorphism and breast cancer susceptibility through meta-analysis, and obtained more accurate and objective conclusion by reducing randomization error and increasing the power of test. ...
Association between ERα gene Pvu II polymorphism and breast cancer susceptibility: A meta-analysis
Article
Full-text available
  • Apr 2018
Background: Estrogen has played an important role in the development of breast cancer. ER-α PvuII gene polymorphism is in close association with the occurrence risk of breast cancer, but no consensus has been achieved currently. Methods: PubMed, Embase, China National Knowledge Infrastructure (CNKI) database, Wanfang database, and VIP database were retrieved to collect the case-control studies on association between ERα gene Pvu II polymorphism and breast cancer risk published before September 1, 2017. Newcastle-Ottawa Scale (NOS) was used to assess the quality of the literatures, Stata 14.0 software was applied for meta-analysis, and the pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated. The subgroup analysis was performed to assess the confounding factors, followed by assessment of publication bias and sensitivity analysis. Results: A total of 26 studies were enrolled in the analysis based on inclusion criteria, which included 15,360 patients and 26,423 controls. The results demonstrated that ERα gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in 3 genetic models (C vs T, OR = 0.962, 95% CI = 0.933-0.992, P = .012; CC vs TT, OR = 0.911, 95% CI = 0.856-0.969, P = .003; CC vs TT/CT, OR = 0.923, 95% CI = 0.874-0.975, P = .004). Subgroup analysis was conducted on the basis of ethnicity and source of controls, whose results illustrated that ERα gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in Asians rather than in Caucasians (CC vs TT, OR = 0.862, 95% CI = 0.750-0.922, P = .038; CC vs TT/CT, OR = 0.851, 95% CI = 0.755-0.959, P = .008). In population-based subgroup rather than in hospital-based subgroup, ERα gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in the allele model, homozygous model, dominant model, and recessive model (C vs T, OR = 0.943, 95% CI = 0.911-0.977, P = .001; CC vs TT, OR = 0.878, 95% CI = 0.817-0.944, P = .000; CC/CT vs TT, OR = 0.936, 95% CI = 0.881-0.994, P = .031; CC vs TT/CT, OR = 0.902, 95% CI = 0.847-0.960, P = .001). Conclusion: ERα gene Pvu II polymorphism exerts an important function in the progression of breast cancer.
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... In addition, two articles were found to contain overlapping data 18,31 , and the one with the smaller sample size was excluded 31 . Ultimately, 22 articles comprising 23 studies were included for the quantitative synthesis of data 3,18,21,24,25,27,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] . ...
... The remaining studies either did not mention the menopausal status or did not perform separate analyses for pre-and postmenopausal women. In terms of ethnicity, nine studies were conducted on Asians 3,18,25,32,34,37,38,41,44 , nine on Caucasian 21,24,27,33,35,36,39,40,47 , three on other ethnicities 43,45,46 , and two on mixed ethnicities 21,42 . All studies were case-control in design. ...
The rs9340799 polymorphism of the estrogen receptor alpha (ESR1) gene and its association with breast cancer susceptibility
Article
Full-text available
  • Sep 2021
The ESR1 rs9340799 polymorphism has been frequently investigated with regard to its association with breast cancer (BC) susceptibility, but the findings have been inconclusive. In this work, we aimed to address the inconsistencies in study findings by performing a systematic review and meta-analysis. Eligible studies were identified from the Web of Science, PubMed, Scopus, China National Knowledge Infrastructure, VIP and Wanfang databases based on the predefined inclusion and exclusion criteria. The pooled odds ratio (OR) was then calculated under five genetic models: homozygous (GG vs. AA), heterozygous (AG vs. AA), dominant (AG + GG vs. AA), recessive (GG vs. AA + AG) and allele (G vs. A). Combined results from 23 studies involving 34,721 subjects indicated a lack of significant association between the polymorphism and BC susceptibility (homozygous model, OR = 1.045, 95% CI 0.887–1.231, P = 0.601; heterozygous model, OR = 0.941, 95% CI 0.861–1.030, P = 0.186; dominant model, OR = 0.957, 95% CI 0.875–1.045, P = 0.327; recessive model, OR = 1.053, 95% CI 0.908–1.222, P = 0.495; allele model, OR = 0.987, 95% CI 0.919–1.059, P = 0.709). Subgroup analyses by ethnicity, menopausal status and study quality also revealed no statistically significant association (P > 0.05). In conclusion, our results showed that the ESR1 rs9340799 polymorphism was not associated with BC susceptibility, suggesting its limited potential as a genetic marker for BC.
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... Not many genetic association studies of BC have been reported in Jordanians, and only a few candidate gene studies have been conducted (AL-Eitan et al., 2017, 2019a, 2019b, 2019c, 2019dAtoum, 2016;Atoum and Foad, 2017). Therefore in the present study, the relationship between the VNTR polymorphism in the SMYD3 gene and BC among Jordanian women was investigated for the first time. ...
Correlation between a variable number tandem repeat (VNTR) polymorphism in SMYD3 gene and breast cancer: A genotype-phenotype study
Article
  • Dec 2019
  • GENE
Genetic predisposition to breast cancer (BC) has become one of the most studied aspects of the disease. Advances in the field of cancer research have revealed the role of different genetic polymorphisms within genes of interest in the development of BC. This study aimed to explore the impact of a variable number tandem repeat (VNTR) genetic variant found within the SET and MYND domain containing protein 3 (SMYD3) gene on BC risk in Jordan and examine key clinical and pathological prognostic factors. Genotyping of blood samples from 180 cases with breast cancer and 180 healthy individuals from the Jordanian population was carried out via a combination of PCR and agarose gel electrophoresis. A highly significant association was found at level of genotype (P-value = 0.009) and allele (P-value = 0.0001) between BC development and the VNTR variant in the SMYD3 gene among Jordanian women. Moreover, we found that the VNTR of SMYD3 gene may interfere with BC risk among patients with different immunohistochemistry (IHC) profiles (P-value < 0.05). This study reported that there is a significant correlation between BC development and the VNTR in the SMYD3 gene. These findings can help alleviate the burden of BC in developing countries including Jordan and to fill the gaps in current literature. Since this study was carried out on Jordanian Arabs, more studies on the link between BC and the SMYD3 VNTR variant are recommended to determine this polymorphism’s impact on other ethnic groups.
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... VDR gene polymorphism plays a major role in the pathogenesis of both systemic and organ-specific diseases. Studying vitamin D level and VDR genetic polymorphisms among RA and QA Jordanians is an important issue because of the high prevalence of vitamin D deficiency among Jordanians which accounts for 76% of Jordanian males and 90% of Jordanian females (15) and because of the lack in the genetics and biochemical studies among Jordanian patients except few studies (16)(17)(18) . Up to our knowledge, this is the first study that measure 25(OH) D among RA and OA patients and determine rs731236(Taq1) gene polymorphism among RA and OA Jordanian patients. ...
VITAMIN D DEFICIENCY AND RS731236(TAQ1) VITAMIN D RECEPTOR GENE POLYMORPHISM AS POSSIBLE RISK FACTORS FOR RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS
Article
Full-text available
  • Jan 2018
  • ACTA MEDICA MEDITERR
Introduction: Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of autoimmune diseases. The role of vitamin D and the vitamin D receptor (VDR) on rheumatic arthritis (RA) and osteoarthritis (OA) health has recently been placed in the spotlight. The aim of this study is to investigate any association between circulating vitamin D level and rs731236 (Taq1) vitamin D receptor gene polymorphism among Jordanian Rheumatic arthritis and osteoarthritis patients. Methods: this study enrolled one hundred and eighty four RA patients, one hundred and fifty four OA patients and two hundred healthy Jordanians from Prince Hamzah Hospital/Amman (2013-2015). 25-hydroxyvitamin D (25 (OH) D) level was determined by competitive immunoassay. DNA was extracted from whole blood for all samples and control, PCR was amplified using specific primers, rs731236 (Taq1) VDR restriction digestion was carried out for Taq1 genotyping Results: 25 (OH) D level was statistically lower among RA and OA patients (12.03± 3.21, 11.88 ± 4.63 ng/mL,) compared to the healthy controls (21.32± 3.12 and 21.51±3.46 ng/mL; respectively). 25 (OH) D within rs731236(Taq1)VDR TT genotype among RA patients (11.67± 3.24) was statistically lower than its control (21.23± 3.43). Statistical difference was found in 25 (OH) D level within TT genotype among the OA patients (12.63±4.31 ng/mL) compared to its control (21.41±3.32 ng/mL). Conclusion: This study showed that there is statistically significant decrease in the mean vitamin D level among both RA and OA patients compared to control, and rs731236(Taq1)VDR TT genotype may be a possible risk factors for both RA and OA.
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... VDR gene polymorphism plays a major role in the pathogenesis of both systemic and organ-specific diseases. Studying vitamin D level and VDR genetic polymorphisms among RA and QA Jordanians is an important issue because of the high prevalence of vitamin D deficiency among Jordanians which accounts for 76% of Jordanian males and 90% of Jordanian females (15) and because of the lack in the genetics and biochemical studies among Jordanian patients except few studies (16)(17)(18) . Up to our knowledge, this is the first study that measure 25(OH) D among RA and OA patients and determine rs731236(Taq1) gene polymorphism among RA and OA Jordanian patients. ...
Vitamin D deficiency and rs731236(Taq1) vitamin D receptor gene polymorphism as possible risk factors for rheumatoid arthritis and osteoarthritis
Article
Full-text available
  • Jan 2018
  • ACTA MEDICA MEDITERR
Introduction: Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of autoimmune diseases. The role of vitamin D and the vitamin D receptor (VDR) on rheumatic arthritis (RA) and osteoarthritis (OA) health has recently been placed in the spotlight. The aim of this study is to investigate any association between circulating vitamin D level and rs731236 (Taq1) vitamin D receptor gene polymorphism among Jordanian Rheumatic arthritis and osteoarthritis patients. Methods: this study enrolled one hundred and eighty four RA patients, one hundred and fifty four OA patients and two hundred healthy Jordanians from Prince Hamzah Hospital/Amman (2013-2015). 25-hydroxyvitamin D (25 (OH) D) level was determined by competitive immunoassay. DNA was extracted from whole blood for all samples and control, PCR was amplified using specific primers, rs731236 (Taq1) VDR restriction digestion was carried out for Taq1 genotyping Results: 25 (OH) D level was statistically lower among RA and OA patients (12.03± 3.21, 11.88 ± 4.63 ng/mL,) compared to the healthy controls (21.32± 3.12 and 21.51±3.46 ng/mL; respectively). 25 (OH) D within rs731236(Taq1)VDR TT genotype among RA patients (11.67± 3.24) was statistically lower than its control (21.23± 3.43). Statistical difference was found in 25 (OH) D level within TT genotype among the OA patients (12.63±4.31 ng/mL) compared to its control (21.41±3.32 ng/mL). Conclusion: This study showed that there is statistically significant decrease in the mean vitamin D level among both RA and OA patients compared to control, and rs731236(Taq1)VDR TT genotype may be a possible risk factors for both RA and OA.
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... [20] Breast cancer research [Downloaded free from http://www.cmj.org on Friday, April 21, 2017, IP: 149.200.187.147] in the Middle East is extremely limited and genetics studies about cancer within Jordan are scarce except for few studies that screen gene polymorphism. [21][22][23][24] To the best of our knowledge, this is a very rare study that showed the association between VDR TaqI genotypes or allelic frequencies among breast cancer patients and controls. This study showed no significant association between VDR TaqI genotypes or allelic frequencies among breast cancer patients and controls. ...
Association between Serum 25‑hydroxy Vitamin D Concentration and TaqI Vitamin D Receptor Gene Polymorphism among Jordanian Females with Breast Cancer
Article
Full-text available
  • May 2017
Background: Breast cancer is the most common type of cancer among females. Genetic polymorphisms might have a role in carcinogenesis. The aim of this study was to determine whether C to T base substitution within TaqI Vitamin D receptor (VDR) gene (rs731236) in exon 9 was a risk factor among patients with breast cancer. Methods: Peripheral blood was drawn from 122 Jordanian breast cancer patients and 100 healthy Jordanian volunteers in Al‑Basheer Hospital during the summer months (from June to November of 2013, 2014, and 2015). DNA was amplified using polymerase chain reaction (PCR), followed by TaqI restriction enzyme digestion. Quantification of serum 25‑hydroxy Vitamin D (25[OH]D) level was determined by competitive immunoassay Elecsys. Results: Genotypic frequencies for TaqI TT, Tt, and tt genotypes were 41%, 46%, and 13% for breast cancer compared to 42%, 50%, and 8% for control, respectively. Vitamin D serum level was significantly lower in the breast cancer patients (8.1 ± 0.3 ng/ml) compared to the control group (21.2 ± 0.6 ng/ml; P = 0.001). This study showed an inverse association between 25(OH)D serum level and breast cancer risk (odds ratio [OR], 22.72, 95% confidence interval [CI], 10.06–51.29). Conclusions: An inverse association was found between 25(OH)D serum level and breast cancer risk. Statistical difference was also found between different VDR TaqI genotypes and circulating levels of 25(OH)D among Jordanian females with breast cancer.
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... [20] Breast cancer research [Downloaded free from http://www.cmj.org on Friday, April 21, 2017, IP: 217.155.195.191] in the Middle East is extremely limited and genetics studies about cancer within Jordan are scarce except for few studies that screen gene polymorphism. [21][22][23][24] To the best of our knowledge, this is a very rare study that showed the association between VDR TaqI genotypes or allelic frequencies among breast cancer patients and controls. This study showed no significant association between VDR TaqI genotypes or allelic frequencies among breast cancer patients and controls. ...
Association between Serum 25-hydroxy Vitamin D Concentration and TaqI Vitamin D Receptor Gene Polymorphism among Jordanian Females with Breast Cancer
Article
Full-text available
  • May 2017
Background: Breast cancer is the most common type of cancer among females. Genetic polymorphisms might have a role in carcinogenesis. The aim of this study was to determine whether C to T base substitution within TaqI Vitamin D receptor (VDR) gene (rs731236) in exon 9 was a risk factor among patients with breast cancer. Methods: Peripheral blood was drawn from 122 Jordanian breast cancer patients and 100 healthy Jordanian volunteers in Al-Basheer Hospital during the summer months (from June to November of 2013, 2014, and 2015). DNA was amplified using polymerase chain reaction (PCR), followed by TaqI restriction enzyme digestion. Quantification of serum 25-hydroxy Vitamin D (25[OH]D) level was determined by competitive immunoassay Elecsys. Results: Genotypic frequencies for TaqI TT, Tt, and tt genotypes were 41%, 46%, and 13% for breast cancer compared to 42%, 50%, and 8% for control, respectively. Vitamin D serum level was significantly lower in the breast cancer patients (8.1 ± 0.3 ng/ml) compared to the control group (21.2 ± 0.6 ng/ml; P= 0.001). This study showed an inverse association between 25(OH)D serum level and breast cancer risk (odds ratio [OR], 22.72, 95% confidence interval [CI], 10.06–51.29). Conclusions: An inverse association was found between 25(OH)D serum level and breast cancer risk. Statistical difference was also found between different VDR TaqI genotypes and circulating levels of 25(OH)D among Jordanian females with breast cancer.
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Linkage Between Obesity Leptin and Breast Cancer
Article
Full-text available
Many cancers might be influenced by obesity, including breast cancer, the leading cause of cancer death among women. Obesity is a complex state associated with multiple physiological and molecular changes capable of modulating the behavior of breast tumor cells and the surrounding microenvironment. This review discussed the inverse association between obesity and breast cancer among premenopausal breast cancer females and the positive association among postmenopausal. Four mechanisms may link obesity and breast cancer including leptin and leptin receptor expression, adipose chronic inflammation, sex hormone alternation, and insulin and insulinlike growth factor 1 (IGF-1) signaling. Leptin has been involved in breast cancer initiation, development, and progression through signaling transduction network. Leptin functions are strengthened through cross talk with multiple oncogenes, cytokines, and growth factors. Adipose chronic inflammation promotes cancer growth and angiogenesis and modifies the immune responses. A pro-inflammatory microenvironment at tumor site promotes cytokines and pro-inflammatory mediators adjacent to the tumor. Leptin stimulates pro-inflammatory cytokines and promotes T-helper 1 responses. Obesity is common of chronic inflammation. In obese patients, white adipose tissue (WAT) will promote pro-inflammatory mediators that will encourage tumor growth and WAT inflammation. Sex hormone alternation of estrogens is associated with increased risk for hormone-sensitive breast cancers. Estrogens cause tumorigenesis by its effect on signaling pathways that lead to DNA damage, stimulation angiogenesis, mutagenesis, and cell proliferation. In postmenopausal females, and due to termination of ovarian function, estrogens were produced extra gonadally, mainly in peripheral adipose tissues where adrenal-produced androgen precursors are converted to estrogens. Active estradiol leads to breast cancer development by binding to ERα, which is modified by receptor’s interaction of various signal transduction pathways. Hyperinsulinemia and IGF-1 activate the MAPK and PI3K pathways, leading to cancer-promoting effects. Cross talk between insulin/IGF and estrogen signaling pathways promotes hormone-sensitive breast cancer development. Hyperinsulinemia is a risk factor for breast cancer that explains the obesity-breast cancer association. Controlling IGF-1 level and targeting IGF-1 receptors among different breast cancer subtypes may be useful for breast cancer treatment. This review discussed several leptin signaling pathways, highlighting the potential advantage of targeting leptin as a potential target of the novel therapeutic strategies for breast cancer treatment.
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The influence of an IL-4 variable number tandem repeat (VNTR) polymorphism on breast cancer susceptibility
Article
Full-text available
  • Aug 2019
Backgrounds Breast cancer (BC) is one of the most widespread cancers globally. Understanding the etiology of BC may help in determining the various risk factors involved in its malignancy. Certain genetic mutations are considered to play a key role in increasing the risk of BC. Objectives In this study, we explored the correlation between a variable number tandem repeat (VNTR) polymorphism in the IL-4 gene and BC. Methods PCR and subsequent gel electrophoresis were used to genotype this variant in 360 Jordanian women (180 BC patients and 180 controls). In addition, phenotype–genotype analysis was carried out. Results Our findings illustrate that there is no significant relationship between the variant genotypes in the IL-4 gene and BC among Jordanian females. Other than body mass index and tumor differentiation (p< 0.05), none of the clinical and pathological parameters of BC patients exhibited any association with the variant genotypes. Conclusions From this study, we propose that the IL-4 genetic variant does not impact BC development and progression but that it could influence the disease prognosis.
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Association of ESR1 polymorphisms (rs3020314 and rs1514348) with breast cancer in Sudanese women. A pilot study
Article
  • Mar 2019
ESR1 encodes estrogen receptor alpha, which mediates estrogen action. Estrogen exposure is a central risk for breast cancer (BC); therefore, ESR1 variants are likely to affect BC susceptibility. We evaluated the association of ESR1 rs3020314 and rs1514348 with BC among Sudanese women, and correlated genotype with BC risk factors and clinicopathologic features. A total of 144 women were recruited in this case-control study (71 women with BC, and 73 healthy controls). ESR1 rs3020314 and rs1643821 –a proxy SNP for rs1514348–were genotyped using PCR-RFLP. Genotype frequencies differed significantly between cases and controls. For rs3020314, women carrying the heterozygous genotype CT had increased BC risk (OR: 2.67; 95%CI: 1.19–6.01; p = 0.02). Conversely, for rs1643821 women with the heterozygous genotype CT showed a decreased BC risk (OR: 0.41, 95%CI: 0.19–0.89; p = 0.02). Allele frequencies were not different between the two groups. In the subgroups of BMI ≥ 25 kg/m² likewise postmenopausal women, patients carrying the rs3020314 genotype CT had 7-times and 6-times BC risk than controls, respectively. There was no association between genotype and clinicopathologic features. Our data suggest that ESR1 rs3020314 and rs1514348 might modify BC risk in Sudanese women. However, these findings need further testing in a larger number of patients.
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ACC interleukin-10 gene promoter haplotype as a breast cancer risk factor predictor among Jordanian females
Article
Full-text available
  • Jun 2016
Introduction: Interleukin-10 (IL-10) is a multifactorial cytokine with a complex biological role in breast cancer. The aims of this study were to investigate any association between IL-10 gene promoter polymorphisms, 1082A>/G, -819T>C, and -592A>C, or haplotypes and breast cancer risk among Jordanian women and to evaluate any association between the most common haplotype with clinicopathological features of breast cancer. Patients and methods: A total of 202 breast cancer patients and 210 age-matched healthy control subjects were genotyped for -1082A/G, -819T/C, and -592A/C single nucleotide polymorphisms in the promoter region of the IL-10 gene by polymerase chain reaction-restriction fragment length polymorphism. Study patients and control subjects were recruited from Prince Hamzah Hospital, Amman, Jordan (2012-2013). Ethical approval and signed consent forms were signed by all participants. DNA was extracted, and polymerase chain reaction fragments were amplified and restriction digested by MnII, MaeIII, and RsaI. Results: This study showed no statistically significant difference between -1082A/G, -819T/C, and -592A/C IL-10 genotypes or alleles among breast cancer patients or controls. Four different haplotypes ATA, ACC, GTA, and ACA within the IL-10 promoter gene were determined among both breast cancer and control groups. The most frequent haplotype was ACC among breast cancer patients and controls (41.6% and 40.7%, respectively). No statistical differences in these haplotypes among breast cancer patients or controls were determined. Analysis of the most common ACC haplotype showed statistical difference in positive estrogen receptor (P=0.022), positive progesterone receptor (P=0.004), cancer grade (P=0.0001), and cancer stage (P=0.009) among the ACC haplotype compared to non-ACC haplotype. Conclusion: To our knowledge, this is the first report studying the association of IL-10 haplotype with breast cancer risk events among Jordanian females. The most frequent IL-10 haplotype among Jordanian breast cancer females is ACC haplotype. Patients carrying the ACC haplotype are associated with higher positive estrogen and progesterone receptors and advanced breast cancer grade and stage. These patients also had lower survival rate in the Kaplan-Meier survival plot compared to those with non-ACC haplotype.
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BRAZILIAN ARCHIVES OF BIOLOGY AND TECHNOLOGY Prevalence of Estrogen Receptor Alpha PvuII (c454-397T>C) and XbaI (c454A>G) Polymorphisms in a Population of Brazilian Women
Article
Full-text available
  • Nov 2011
The aim of this work was to study the estrogen receptor alpha (ERS1) PvuII and XbaI gene polymorphisms prevalence in randomly selected women population from Rio de Janeiro and Espírito Santo states in Brazil by polymerase chain reaction restriction fragment lengths polymorphism (PCR_RFLP) methodology. It was shown that Rio de Janeiro women exhibited a significantly different prevalence of XbaI polymorphism comparing to Espirito Santo women. Nonetheless, similar prevalence of PvuII polymorphism was found in both women´s populations. Moreover, a strong linkage disequilibrium was observed between these SNPs reinforcing the hypothesis of differential pattern of inheritance observed on such populations.
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The Fok1 Vitamin D Receptor Gene Polymorphism and 25(OH) D Serum Levels and Prostate Cancer among Jordanian Men
Article
Full-text available
  • Apr 2015
  • ASIAN PAC J CANCER P
cause of cancer death in men in the Western world. Vitamin D (1,25dihydroxy vitamin D) is linked to many biological processes that influence oncogenesis but data on relations between its genetic variants and cancer risk have been inconsistent. The aim of this study was to determine associations between a vitamin D genetic polymorphism and 25-hydroxyvitamin D [25(OH)D] levels and prostate cancer. Materials and Methods: Genomic DNA was extracted from 124 Jordanian prostate cancer patients and 100 healthy volunteers. Ethical approval was granted from the ethical committee at Hashemite University and written consent was given by all patients. PCR was used to amplify the vitamin D receptor Fok1 polymorphism fragment. 25(OH)D serum levels were measured by competitive immunoassay. Results: All genotypes were in Hardy-Weinberg equilibrium. Genotype frequency for Fok1 genotypes FF, Ff and ff was 30.7%, 61.3% and 8.06%, for prostate cancer patients, while frequencies for the control group was 28.0%, 66.0% and 6.0%, respectively, with no significant differences. Vitamin D serum level was significantly lower in prostate cancer patients (mean 7.7 ng/ml) compared to the control group (21.8 ng/ml). No significant association was noted between 25(OH)D and VDR Fok1 gene polymorphism among Jordanians overall, but significant associations were evident among prostate cancer patients (FF, Ff and ff : 25(OH)D levels of 6.2, 8.2 and 9.9) and controls (19.0, 22.5 and 26.3, respectively). An inverse association was noted between 25(OH)D serum level less than 10ng/ml and prostate cancer risk (OR 35.5 and 95% CI 14.3- 88.0). Conclusions: There is strong inverse association between 25(OH)D serum level less than 10ng/ml level and prostate cancer risk
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Association between Circulating Vitamin D, the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians
Article
Full-text available
  • Sep 2014
  • ASIAN PAC J CANCER P
Background: The physiological role of vitamin D extends beyond bone health and calcium-phosphate homeostasis to effects on cancer risk, mainly for colorectal cancer. Vitamin D may have an anticancer effect in colorectal cancer mediated by binding of the active form 1,25(OH)2D to the vitamin D receptor (VDR). The Taq1 VDR gene polymorphism, a C-to-T base substitution (rs731236) in exon 9 may influence its expression and function. The aim of this study was to determine the 25(OH)D vitamin D level and to investigate the association between circulating vitamin D level and Taq1VDR gene polymorphism among Jordanian colorectal cancer patients. Materials and methods: This case control study enrolled ninety-three patients and one hundred and two healthy Jordanian volunteers from AL-Basheer Hospital/Amman (2012-2013). Ethical approval and signed consent forms were obtained from all participants before sample collection. 25(OH)D levels were determined by competitive immunoassay Elecsys (Roche Diagnostic, France). DNA was extracted (Promega, USA) and amplified by PCR followed by VDR Taq1 restriction enzyme digestion. The genotype distribution was evaluated by paired t-test and chi-square. Comparison between vitamin D levels among CRC and control were assessed by odds ratio with 95% confidence interval. Results: The vitamin D serum level was significantly lower among colorectal cancer patients (8.34 ng/ml) compared to the healthy control group (21.02 ng/ml). Patients deficient in vitamin D (less than 10.0 ng/ml) had increased colorectal cancer risk 19.2 fold compared to control. Only 2.2% of CRC patients had optimal vitamin D compared to 23.5% among healthy control. TT, Tt and tt Taq1 genotype frequencies among CRC cases was 35.5%, 50.5% and 14% compared to 43.1%, 41.2% and 15.7% among healthy control; respectively. CRC patients had lower mean vitamin D level among TT (8.91 ± 4.31) and Tt (9.15 ± 5.25) genotypes compared to control ((21.3 ± 8.31) and (19.3 ± 7.68); respectively. Conclusions: There is significant association between low 25(OH)D serum level and colorectal cancer risk. The VDRTaq1 polymorphism was associated with increased colorectal cancer risk among patient with VDRTaq1 TT and Tt genotypes. Understanding the functional mechanism of VDRTaq1 TT and Tt may provide a strategy for colorectal cancer prevention and treatment.
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Conservation in first introns is positively associated with the number of exons within genes and the presence of regulatory epigenetic signals
Article
Full-text available
  • Jun 2014
  • BMC GENOMICS
Background Genomes of higher eukaryotes have surprisingly long first introns and in some cases, the first introns have been shown to have higher conservation relative to other introns. However, the functional relevance of conserved regions in the first introns is poorly understood. Leveraging the recent ENCODE data, here we assess potential regulatory roles of conserved regions in the first intron of human genes. Results We first show that relative to other downstream introns, the first introns are enriched for blocks of highly conserved sequences. We also found that the first introns are enriched for several chromatin marks indicative of active regulatory regions and this enrichment of regulatory marks is correlated with enrichment of conserved blocks in the first intron; the enrichments of conservation and regulatory marks in first intron are not entirely explained by a general, albeit variable, bias for certain marks toward the 5’ end of introns. Interestingly, conservation as well as proportions of active regulatory chromatin marks in the first intron of a gene correlates positively with the numbers of exons in the gene but the correlation is significantly weakened in second introns and negligible beyond the second intron. The first intron conservation is also positively correlated with the gene’s expression level in several human tissues. Finally, a gene-wise analysis shows significant enrichments of active chromatin marks in conserved regions of first introns, relative to the conserved regions in other introns of the same gene. Conclusions Taken together, our analyses strongly suggest that first introns are enriched for active transcriptional regulatory signals under purifying selection. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-526) contains supplementary material, which is available to authorized users.
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Prevalence of estrogen receptor alpha PvuII (c454-397T>C) and XbaI (c454A>G) polymorphisms in a population of Brazilian women
Article
Full-text available
  • Dec 2011
  • BRAZ ARCH BIOL TECHN
The aim of this work was to study the estrogen receptor alpha (ERS1) PvuII and XbaI gene polymorphisms prevalence in randomly selected women population from Rio de Janeiro and Espírito Santo states in Brazil by polymerase chain reaction restriction fragment lengths polymorphism (PCR_RFLP) methodology. It was shown that Rio de Janeiro women exhibited a significantly different prevalence of XbaI polymorphism comparing to Espirito Santo women. Nonetheless, similar prevalence of PvuII polymorphism was found in both women´s populations. Moreover, a strong linkage disequilibrium was observed between these SNPs reinforcing the hypothesis of differential pattern of inheritance observed on such populations.
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Identification of estrogen receptor proteins in breast cancer cells using matrix-assisted laser desorption/ionization time of flight mass spectrometry (Review)
Article
Full-text available
  • May 2014
Estrogen receptors [ERs (subtypes α and β)], classified as a nuclear receptor super family, are intracellular proteins with an important biological role as the transcription factors for estrogen target genes. For ER-induced transcription, an interaction must exist between ligand and coregulators. Coregulators may stimulate (coactivators) or inhibit (corepressors) transcription, following binding with a specific region of the gene, called the estrogen response element. Misbalanced activity of coregulators or higher ligand concentrations may cause increased cell proliferation, resulting in specific types of cancer. These are exhibited as overexpression of ER proteins. Breast cancer currently ranks first in the incidence and second in the mortality of cancer in females worldwide. In addition, 70% of breast tumors are ERα positive and the importance of these proteins for diagnostic use is indisputable. Early diagnosis of the tumor and its classification has a large influence on the selection of appropriate therapy, as ER-positive tumors demonstrate a positive response to hormonal therapy. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI TOF MS) has been hypothesized to have great potential, as it offers reliable, robust and efficient analysis methods for biomarker monitoring and identification. The present review discusses ER protein analysis by MALDI TOF MS, including the crucial step of protein separation.
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Genetic polymorphisms in the estrogen receptor alpha gene and risk of breast cancer: Results from the Shanghai breast cancer study
Article
  • Sep 2003
Estrogen receptor (ER) is a ligand-activated transcription factor that mediates estrogen actions in target tissues. Several common polymorphisms of the ER-alpha gene have been reported to be associated with alterations in receptor expression and function. We evaluated the hypothesis that genetic polymorphisms in the ER-alpha gene may be associated with breast cancer risk in a population-based case-control study conducted in urban Shanghai during 1996-1998. Two RFLPs at the ER-alpha gene locus, denoted as PvuII and XbaI, were examined in 1069 breast cancer cases and 1166 age frequency-matched controls. PvuII polymorphism was associated with an increased risk of breast cancer with the age-adjusted odds ratios for genotypes Pp and pp being 1.3 [95% confidence interval (CI), 1.0-1.7) and 1.4 (95% CI, 1.1-1.8), respectively, comparing to genotype PP. The XbaI polymorphism was associated with a nonsignificantly elevated risk. The odds ratios for genotypes Xx and xx were 1.2 (95% CI, 0.7-1.9) and 1.3 (95% CI, 0.8-2.0), respectively, and the elevated risks were mainly confined to older or postmenopausal women. No apparent synergetic effect of these two polymorphisms was identified. Results of this study indicate that genetic polymorphisms in the ER-alpha gene may play a role in the etiology of breast cancer.
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Emerging EGFR antagonists for breast cancer
Article
  • May 2014
  • EXPERT OPIN EMERG DR
Introduction: The EGFR has been associated with the pathogenesis and progression of breast cancer. Treatment based on an EGFR target is emerging as a promising option, especially in combination with conventional therapies. Unfortunately, there are no validated predictor biomarkers, and combinatorial treatments are meeting new resistance. Areas covered: The purpose of this review is to summarize the existing treatments and the current research based on targeting the EGFR pathway. Expert opinion: The existing EGFR treatments in breast cancer have shown limited benefit. The combination of the monoclonal antibody cetuximab and platinum salts achieves a 15 - 20% response rate. The effectiveness of tyrosine kinase inhibitors is not completely clear, showing modest or no benefits. Gefitinib treatment has offered some promising results in estrogen receptor + breast cancer. However, it has not been identified as a predictive factor for the appropriate selection of patients. Radioimmunotherapy with anti-EGFR radiolabeled antibodies is a promising strategy in BRCA-mutated breast cancer, but it still requires clinical confirmation. Nevertheless, the crosstalk between pathways frequently leads to treatment resistance. Current research is focused on increasing knowledge about the mechanisms of response and the discovery of predictive markers. Targeting several pathways simultaneously and a correct selection of patients seem essential.
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