bio markers in women with breast cancer: ii
TRANSCRIPT
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Abdulghani et al. World Journal of Pharmacy and Pharmaceutical Sciences
BIO MARKERS IN WOMEN WITH BREAST CANCER: II
HORMONES, CALCIUM, VIT D, GLUCOSE AND IGF PREDICTIVE
VALUE
Amina Hamed Alobaidi, Arzu Jalaly, Abdulghani Mohamed Alsamarai*, Hamid Hindi
Sarhan.
Departments of Biochemistry, Medicine and Surgery, Tikrit University College of
Medicine, Tikrit, Iraq.
ABSTRACT
Background: Breast cancer is the most commonly diagnosed cancer
among Iraqi women. Many factors proposed as risk factor for the
development of breast cancer. Aim: To examine the relationship
between some circulating markers and breast cancer risk. Patients and
Methods: 100 women with breast cancer and 100 healthy controls
were included in the study. All patients and control groups serum
samples were subjected for determination of progesterone receptor,
estrogene receptor, PTH, insuline growth factor, Vit D, prolactin,
progesterone, estrogen, HBA1C , Blood sugar and calcium. Results:
Serum mean values of prolactin, progesterone receptor, estrogene
receptor, glucose, HBA1C, and calcium were significantly higher in
women with breast cancer than in controls. While circulating estrogene, progesterone, IGF-1,
PTH, and vit D mean values were significantly lower in breast cancer than in controls. OR
confirm the association between the tested markers and breast cancer. Conclusion: This
study indicated a significant association between breast cancer and serum levels of prolactin,
progesterone, estrogene, progesterone receptor, estrogene receptor , sugar, HBA1C, insuline
growth factor , Ca+2
, Vit. D and PTH, However, AUC of ROC indicated the low predictive
value of estrogene and progesterone.
KEYWORDS: Progesterone Receptor, Estrogen Receptor, PTH, Insuline Growth Factor, Vit
D, prolactin, progesterone, estrogen, HBA1C, Blood sugar and calcium, breast cancer.
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Article Received on
04 June 2015,
Revised on 25 June 2015,
Accepted on 13 July 2015
*Correspondence for
Author
Professor Abdulghani
Alsamarai
Department of Medicine,
Tikrit University College
of Medicine, Tikrit, Iraq
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INTRODUCTION
For decades the clinicians and research scientist are interested in the concept of early
detection of various forms of cancer before their metastasis.[1]
This is essntial since 40% of
breast cancer at the time of diagnosis were spread from their primary site.[2]
Thus early
detection will influence the mortality, morbidity and economic burden of breast cancer.[1]
Tumor marker detection may help to early diagnosis, plan and therapy monnitoring and
disease prognosis guidance, however not every marker is appropriate for every stage of breast
cancer.[3,4]
Although, CA15-3, CEA, and CA27-29 are the most widely investigated tumor markers in
women with breast cancer.[3,5]
other biomarkers emerged for prognosis and prediction of
breast cancer.[6]
These include estrogen receptor, progesteron receptor, oncoproteins, p53,
Ki67, Cyclin D1, Cyclin E,Erβ, circulating tumor cell, and tumor specific –DNA, CXCR4,
caveolin, miRNA, FOXP3, osteopontin, PTEN, h-MAM, FGFR2 and others.[6,7,8]
Cancer etiology not yet fully understood and many hypothesis are proposed.[9]
Previous
studies reported that HBA1C.[10-14]
Insulin like growth factor,[15-19]
Prolactin.[4,20-23]
Progesteron.[4,22,24]
Estrogene.[4,22,25]
Glucose [26-30] Calcium.[31-33]
Parathyroid
hormone[32,34-36]
and Vitamin D.[31,32]
were a risk factors for breast cancer. Reproductive
hormones, specifically estrogen and progesteron, play a critical role in etiology of breast
cancer.[37]
Estrogen and progesteron receptors do influence the prognosis ob breast
cancer.[4,6,38-44]
Estrogen receptor is a strong predictor of clinical response to hormonal
therapy.[45]
Reported studies suggest that prolactin , estrogen, progesteron, growth hormone
and corticosteroids are the main hormones that play role in development of breast
cancer,[22,46]
In this study the role of prolactin, progesterone, Sugar,HBA1C,Insuline Growth
Factor, Ca+2
, Vit. D and PTH as risk factor in women with breast cancer were studies.
Progesterone and Estrogen Receptors also determined in patients serum to illustrate their
association with breast cancer.
MATERIALS AND METHODS
Study population
Hundred patients diagnosed as with breast cancer patients were included in the study. They
were recruted from women attending Breast Clinic in Azadi Hospital in Kirkuk during the
period from December 2012 till the end of May 2013. All patients were female, their ages
ranged from 35-74 years. Aapparently healthy 100 women were selected as control group.
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All patients and control groups serum samples were subjected for determination of prolactin,
progesterone, Estrogen, progesterone Receptor, Estrogen Receptor , Sugar,HBA1C,Insuline
Growth Factor , Ca+2
, Vit. D and PTH. The study protocol was approved by the ethical
committee of Tikrit University College of Medicine and informed consent taken from each
women agreed to participate in the study.
Methods
Serum progesterone Receptor, Estrogen Receptor, PTH, Insuline Growth Factor and Vit D
were determined by ELISA. While serum prolactin, progesterone, Estrogen were determined
using VIDAS. HBA1C was dertemined using i·CHROMAl HbAlC Test. Blood sugar and
calcium were determined by colorimetric method.
Statistical analysis
The results presented as mean ± SD and comparsion between patients and control groups
performed usig SPSS (version 16) statistical package. P value of <0.05 considered
significant. Odd ratio calculated using international standards and the present study control
figures of mean values of the determined markers.
RESULTS
The mean serum Prolactien was significantly (P<0.0001) higher in patients with breast
cancer (45.65 ± 9.07 ng/ml) compared to control (18.50± 7.21 ng/ml) .Thus the mean value
was about 2.5 times higher in patients than in controls, table (1). Odd ratio confirmed a
significant association between increased Prolactien serum level and Breast cancer for both
international standard (OR = 22.4, p< 0.0001) and present study control (OR = 25.81, p<
0.0001), Table 1.
The mean serum Progesterone was significantly (P<0.0001) lower in patients with breast
cancer (2.06 ± 2.56 ng/ml) compared to control (6.12± 3.60 ng/ml). Thus the mean value was
about three times higher in controls than in patients with breast cancer, table (2).
The mean serum Estrogene was significantly (P<0.0001) lower in patients with breast cancer
(44.28 ± 31.71 pg/ml) compared to control (98.49±44.79 pg/ml) .Thus the mean value was
about two times higher in controls than in patients, table (3).
The mean serum Progesterone Receptor was significantly (P<0.0001) higher in patients with
breast cancer (19.98 ± 9.38 ng/ml) compared to control (4.74± 1.92 ng/ml). Thus the mean
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value was about five times higher in patients than in controls, table (4). Odd ratio confirmed
the significant association between serum Progesterone Receptor increased serum levels and
Breast cancer for international standard (OR = 32.02, p< 0.0001) and this study control
(OR = 23, p< 0.0001), table (4).
The mean serum Estrogene Receptor was significantly (P<0.0001) higher in patients with
breast cancer (629.86 ± 152.273 pg/ml) compared to control (346.41± 74.28 pg/ml) .Thus the
mean value was about three times higher in patients than in controls, table (5) . Increase in
Estrogene Receptor serum level significantly (P<0.0001) associated with breast cancer for
both standards for international (OR = 56.64), for this study control (OR = 32), table (5).
The mean serum Glucose was significantly (P<0.0001) higher in patients with breast cancer
(164.41± 103.58 mg/dl) compared to control (100.38±14.67 mg/dl), table (6). Odd ratio
confirmed the association between increase in blood Glucose levels and breast cancer using
both international standard (OR = 75, p< 0.0001) and present study control (OR = 2.32, p<
0.0001), table (6).
The mean serum HBA1C was significantly (P<0.0001) higher in patients with breast cancer
(5.62± 3.53 %) compared to control (4.11 ±1.28%),table (7). Odd ratio indicated that HBA1C
may be a risk factor in women with breast cancer whether using international standard (OR =
5.44, p< 0.0001) or present study control (OR = 3.21, p< 0.0006), table (7).
The mean serum IGF was significantly (P<0.0001) lower in patients with breast cancer
(197.02± 112.13 ng/ml) compared to control (307.09 ±82.54 ng/ml), table (8). Odd ratio
confirmed significantly association between reduction in serum IGF and breast cancer for
both international standard (OR = 27.56, p< 0.0001) and this study control (OR = 42.35, p<
0.0001), table (8). However, none of the subjects included in the study (cases and control)
show a serum level higher than cut-off value of IGF-1. In addition, 36% and 2% are with
serum value of lower than the lower limit of cut-off in women with b reast cancer and
controls respectively.
The mean serum Calcium was significantly (P<0.0001) higher in patients with breast cancer
(12.84± 1.93 mg/dl) compared to control (9.00 ±0.75 mg/dl), table (9). The increase serum
Calcium levels significantly association with breast cancer using international standard (OR =
91, p< 0.0001) or present study control (OR = 86.55, p< 0.0001) , table (9).
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The mean serum PTH was significantly (P<0.0001) higher in patients with breast cancer
(6.36 ± 2.64 ng/ml ) compared to control (38.63 ±17.30 ng/ml) .Thus the mean value was
about six times higher in patients than in controls, table (10) . Reduction in serum PTH
levels was significantly associated with breast cancer using international standard ( OR =
103, p< 0.0001) or present study control (OR = 57.61 , p< 0.0001), table (10).
The mean serum Vit. D was significantly (P<0.0001) higher in patients with breast cancer
(6.3 ± 2.43 ng/ml) compared to control (39.55 ±17.10 ng/ml) .Thus the mean value was
about six times lower in patients than in controls, table (11). Odd ratio confirmed that Vit. D
serum level reduction was a risk factor in women with breast cancer using international
standard (OR =194, p< 0.0001) and this study control (OR = 57.61, p< 0.0001), table (11).
Area under curve of ROC indicated a highly significant association between breast cancer
and increased circulating prolactin (0.999), calcium (0.992), progesterone receptor (0.912),
and estrogene receptor (0.93). While a modest association found with glucose (0.621) and
HBA1C (0.557). A high significant association revealed between breast cancer and decreased
circulating PTH (0.999) and vitamin D (0.999), Table 12.
Table (1) Mean Prolactien in patients with breast cancer compared to control.
Variable Mean ± SD
Prolactin ng/ml
Patient 45.65±9.077
Control 18.50±7.211
t test 23.41
P value <0.0001
Cut-off ng/ml
International
standard
Present study
control
35
Odd ratio
[95% CI]
22.4
[10.63-47.24]
25.81
[12.20-54.62]
Z statistic 8.169 8.50
P value <0.0001 <0.0001
Relative risk 4.22 4.72
Table (2) Mean Progesterone in patients with breast cancer compared to control.
Variable Progesterone ng/ml
Patient Control
Mean (x-) 2.061 6.12
St.D (±) 2.561 3.605
t-Test 9.17
p-value <0.0001
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Table (3) Mean Estrogene in patients with breast cancer compared to control.
Table (4) Mean Progesterone receptor in patients with breast cancer compared to
control.
Variable Mean ± SD
Progesterone
receptor ng/ml
Patient 19.98±9.38
Control 4.74±1.92
t test 15.90
P value <0.0001
Cut-off in ng/ml
International
standard
Present study
control
10 6.66
Odd ratio
95% CI
32.02
[14.04-73.02]
23.10
[11.00-48.54]
Z statistic 8.241 8.290
P value <0.0001 <0.0001
Relative risk 8.44 4.1
Table (5) Mean Estrogene Receptor and odd ratio in patients with breast cancer
compared to control.
Variable Mean ± SD
Estrogene receptor
ng/ml
Patient 629.86±152.27
Control 346.41±74.28
t test 16.73
P value <0.0001
Cut-off ng/ml
International
standard
Present study
control
500 420.69
Odd ratio
[95%CI]
56.64
[22.65-141.61]
32.25
[14.82-70.19]
Z statistic 8.634 8.75
P value <0.0001 <0.0001
Relative risk 11.57 5.37
Variable Estrogene pg/ml
Patient control
Mean (x-) 44.28 98.49
St.D (±) 31.711 44.793
t-Test 9.877
p-value <0.0001
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Table (6) Mean Glucose and odd ratio in patients with breast cancer compared to
control
Variable Mean ± SD
Glucose mg/dl
Patient 164.41±103.58
Control 100.38±14.67
t test 6.12
P value <0.0001
Cut-off mg/dl
International
standard
Present study
control
120 115.05
Odd ratio
[95%CI]
5.75
[2.67-12.39]
2.31
[1.26-4.29]
Z statistic 4.47 2.70
P value <0.0001 <0.0001
Relative risk 3.9 1.78
Table (7) Mean HBA1C and odd ratio in patients with breast cancer compared to
control.
Variable Mean ± SD
HBA1C %
Patient 5.62±3.53
Control 4.11±1.28
t test 4.03
P value <0.0001
Cut-off %
International
standard
Present study
control
6 5.39
Odd ratio
[95% CI]
5.44
[2.45-12.10]
3.21
[1.65-6.29]
Z statistic 4.15 3.41
P value <0.0001 <0.0001
Relative risk 3.9 2.37
Table (8) Mean IGF and odd ratio in patients with breast cancer compared to control
Variable Mean ± SD
IGF-1 ng/ml
Patient 197.02±112.13
Control 307.09±82.54
t test 7.90
P value <0.0001
Cut-off ng/ml
International
standard
Present study
control
135 389.63
Odd ratio
[95% CI]
27.56
[6.41-118.48]
42.35
[16.61-107.10]
Z statistic 4.45 7.84
P value <0.0001 <0.0001
Relative risk 18 3.48
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Abdulghani et al. World Journal of Pharmacy and Pharmaceutical Sciences
Table (9) Mean serum Calcium and odd ratio in patients with breast cancer compared
to control
Variable Mean ± SD
Calcium mg/dl
Patient 12.84±1.93
Control 9.00±0.75
t test 5.27
P value <0.0001
Cut-off mg/dl
International
standard
Present study
control
10.5 9.75
Odd ratio
[95% CI]
91
[35.31-234.48]
86.55
[30.78-243.4]
Z statistic 9.341 8.456
P value <0.0001 <0.0001
Relative risk 10.98 5.27
Table (10) Mean PTH and odd ratio in patients with breast cancer compared to control
Variable Mean ± SD
PTH ng/ml
Patient 6.36±2.64
Control 38.63±17.30
t test 18.43
P value <0.0001
Cut-off ng/ml
International
standard
Present study
control
<10 55.93
Odd ratio
[95% CI]
103
[39-274]
57.61
[3.44-964.60]
Z statistic 9.336 2.81
P value <0.0001 <0.0001
Relative risk 11.27 1.28
Table (11) Mean Vit D and odd ratio in patients with breast cancer compared to control
Variable Mean ± SD
Vit D ng/ml
Patient 6.3±2.43
Control 39.55±17.10
t test 19.24
P value <0.0001
Cut-off ng/ml
International
standard
Present study
control
<10 56.65
Odd ratio
[95% CI]
194
[59-632]
57.61
[3.44-964.60]
Z statistic 8.750 2.81
P value <0.0001 <0.0001
Relative risk 8.7 1.28
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Table 12. Area Under Curve (AUC) as a Predictive of Biomarkers in Patients with
Breast Cancer.
Biomarker AUC [95% CI] Standard Error
Prolactin 0.999 [0.997-1.001] 0.001
Progesteron 0.149 [0.094-0.204] 0.028
Estrogen 0.168 [0.114-0.222] 0.028
Progesteron receptor 0.912 [0.868-0.955] 0.022
Estrogen receptor 0.930 [0.891-0.969] 0.020
Glucose 0.621 [0.542-0.699] 0.040
HBA1C 0.557 [0.474-0.640] 0.042
IGF 0.233 [0.169-0.298] 0.033
Calcium 0.992 [0.983-1.00] 0.004
PTH 0.999[0.997-1.001] 0.001
Vit D 0.999[0.997-1.001] 0.001
DISCUSSION
Epidemiological and experimental studies suggest that prolactin, estrogen and progesteron
may play a role in the etiology of breast cancer.[20,22,23]
The present study indicated that serum
mean concentration of prolactin, progesteron and estrogene was 2-3 times are higher in
women with breast cancer than those in controls. The association between serum prolactin
levels and presence of breast cancer was confirmed by high odd ratio and area under ROC
curve.
Vonderhaar.[20]
suggests that prolactin is involved in breast cancer development. Prolactin is
induced locally by breast cancer cells.[47]
and associated with higher cellular motility and
angiogenesis.[48]
These evidence confirmed by the present study finding that confirm the
association of prolactin and development of breast cancer. Tworoger et al.[49]
and Atoum et
al.[4]
suggest a significant association of serum prolactin and risk of breast cancer
development. In a recent study, Tikk et al.[23]
reported that higher circulating prolactin levels
among the postmenopausal hormone replacement therapy users may be associated with
increased risk of development of breast cancer. Other studies addressed the possible
associations between risk of breast cancer and serum prolactin levels.[50-54]
Two large scale
studies indicated a modest positive risk association between breast cancer and serum
prolactin levels among postmenopausal but not among premonopausal women.[50,55]
Progesterone and estrogene implicated as with critical roles for development and progression
of breast cancer.[56]
Estrogene and progesterone do play a roles in breast cancer intiation and
may play a role in breat cancer prevention based on that full term pregnancy lead to a
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significant reduction in breast cancer.[25]
However, reduction of estrogene and progesterone
might be helpful in prventing devrlopment of brest cancer.[22]
The impact of progesterone on breast cancer development in literature is contradictory and
the effect of exogenous type on breast tissue may be proliferative or antipriliferative .[57-61]
This confirmed by the present study finding that found progesterone serum mean
concentration was 3 times lower in women with breast cancer. A finding that goes with
suggestion of Jerry.[25]
concerning the preventive role of serum progetsterone in breast
cancer.
Anti – estrogen drug use leads to reduction of breast cancer compared to those who did not
use the drug.[62]
It may be postulated that hormones and genetic together rather than each
alone, play a synergisic effect that inhance development of breast cancer.
Progesterone and its receptor are implicated in the development and progression of breast
cancer.[24,39-41,44]
The present study shows that serum progesteron concentration in women
with breast cancer was 3 times lower than that in controls, while estrogen mean serum
concentration was 2 times higher than in controls. However, area under curve of ROC was
much lower than accepted significant cut-off (AUC =0.50) for both estrogene and
progesterone serum concentration.
Both progesterone and estrogene exert their functions through activation of progesterone
(PR) and estrogene (ER) receptors respectively.[63]
Phetypic classificantion of breast cancer
and therapeutic prediction are based on these two receptors (PR & ER) with human epidermal
growth factor receptor 2 (HER2).[64,65]
In 60 % of the present study population there are
concomittant increase in serum PR and ER concentration in the same patients with breast
cancer. These finding confirmed the previously reported studies.[64,66]
Our cohort study show
five times PR serum concentration in women with breast cancer as compared to controls. OR
confirmed the positive association between increase in serum PR concentration and breast
cancer using international standard or our study control cutt-off values.Furthermore, AUC of
ROC curve was highly significant (AUC= 0.912) in women with breast cancer. This goes
with animal model and clinical trial studies that suggest progesterone play a major role in
development and growth of breast cancer throught it PR receptor, however, estrogen-driven
endometrial cancer inhibited by PR.[67,68]
Recent reviewes suggest that estrogene and
progesterone play a role in development of breast cancer through their receptors.[42,69-72]
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Abdulghani et al. World Journal of Pharmacy and Pharmaceutical Sciences
The American Society of Clinical Oncology and the College of American Pathologist
guideline has the aim to improve hormone receptor testing for women with breast cancer and
recommend progesterone and estrogen recptors determination in all newly diagnosed breast
cancer cases and in recurrent cases.[73]
Progesterone receptor expression is strongly
dependent on the presence of estrogene receptor.[7]
Thus concomittant positivity of high PR
and ER in our cohort may confirm sucus concomittant positivity of high PR and ER in our
cohort may confirm such suggestion. In a recent study Khushi et al.[41]
propoised the evidence
of biologically relevant interplay between estrogene receptor and progesterone receptor in a
subset of binding sitesin breast cancer cells. Hefti et al.[40]
reported that estrogene receptor
negative/progesterone receptor positive breast cancer is not a reproducible subtype. However,
this study indicated that 14% of women with breast cancer are progesterone positive but are
estrogen receptor negative. Ritte et al.[44]
provide possible evidence that age of menarche and
the duration between menarche and 1st full term childbirth may be associated with the
etiology of both hormone negative and hormone positive malignancies. Both estrogene and
progesterone receptors are a novel target for preventive approach of breast cancer.[24]
The major complication in breast cancer treatment is the resistance to chemotherapy,[21]
The
potential crosstalk between estrogen and prolactin in conferring resistance to cheotherapy for
breast cance is suggested. Thus a reduction in the ability of these two hormones to confer
their chemoresistance should enhance the treatment and prevention of breast cancer and new
drug availability. [21]
Both diabetes and breast cancer are common disease with worldwide distribution with high
mortality and morbidity and up to 16% of breast cancer in old age are associated with
diabetes.[29]
In large population based study in postmenopausal women with breast cancer
survivors indicated a high incidence of diabetes. [74]
The present study finding indicated that
mean serum glucose was significantly higher in women with breast cancer than in controls. In
addition, OR confirmed a significant association between breast cance and increase in
glucose blood concentration using both international standard or present study control as cut-
off value.
Association between breast cancer and diabetes may be contributed by altered regulation of
adipocytokines, altered regulation of endogenous sex hormones, activation of insulin-like
growth factor pathway, and activation of the insulun pathway.[29]
These four mechanisms
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Abdulghani et al. World Journal of Pharmacy and Pharmaceutical Sciences
may act synergistically to induce increase in proliferation, invasivness, angiogenesis and
apoptosis reduction.
Larsson et al in a meta-analysis study that include 23 studies indicated that diabetes is
associated with an increased risk of breast cancer.[14]
Liao et al.[30]
in a meta analysis of 12
studies that included 730,069 suggest that diabetes is a risk factor for breast cancer.
Boyle et al.[75]
reported that breast cancer risk in women with type 2 diabetes increased by
27% in a meta-analysis study that included 40 studies. Diabetes mellitus and obesity are
suggested as risk factor for breast cancer in female.[27]
The prediabetic and diabetic women
should be considered a more vulnerable population for early breast cancer detection.[76]
Lipscombe et al.[77]
in a large scale study that included a 38,407 women reported that diabetes
may predispose to more aggressive breast cancer.
Treatment of diabetes with metformin in women with breast cancer may be with promise
results for improving outcomes of the disease.[78]
In a recent study Kim et al. [79]
suggested that patients receiving metformin treatment when
breast cancer diagnosis show a better prognosis only if they have hormone –receptor positive.
Chronic hyperglycemia as detected by HbA1C was associated with survival reduction in
women with early stage breast cancer.[28,11]
Our study shows that 35% of women with breast
cancer are with >6% of HbA1C, while the corresponding value in control is 9%. OR ratio
confirmed the association chronic hyperglycemia as monitored by determination of HbA1C
with breast cancer. In addition, the mean serum of HbA1C was significantly higher in women
with breast cancer compared to controls. Jousheghany et al.[10]
found that there are no
significant relationship between HbA1C levels and breat tumor stage. However, there may
be clinically meaningful relationship based on observed trends.
Recent review.[80]
reported that IGF -1 play a role in breast cancer. Our present study finding
indicated that serum IGF-1 was higher than 500 ng/ml in 36% of women with breast cancer
and only in 2% in control with an odd ratio of 28 (P<0.0001. However the mean serum value
was significantly lower in breast cancer than control. In literature a conflicting results were
reported by different studies which may be due to tumor heterogenicity and genetic variation
between the studied population, methodologicals approaches and tumor distinct molecular
subtypes.[80]
Peyrat et al.[81]
reported the initial work that suggest the association between
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IGF-1 and breast cancer as they found high circulating plasma IGF-1 in premenopausal but
not in postmenopausal women
Hankinson et al.[82]
reported an association between IGF-1 and breast cancer in
premenopausal but not postmeopausal breast cancer, but other studies based on a large scale
population did not support an association between breast cancer and circulating IGF-1 in
premenopausal women.[83-85]
The Endogenous Hormones and Breast Cancer Collaborative Group found an association
between breast cancer and circulating IGF-1 in estrogen receptor positive tumors independent
of menopausal status .[86]
The European Prospective Investigation into Cancer and Nutrition
cohort supported the abov finding.[87]
In women with BRCA mutation, serum IGF-1 was positively associated with increased breast
cancer risk in an Italian population.[88]
In contrast, other studies not found a correlation
between breast cancer development and IGF-1 concentration in Brazilian women [89] or
women during early pregnancy.[90]
An association between mamographic density (as breast
tumor predictor) and IGF-1 serum level was reported in one study,[91]
but this finding not
confimed by a recent studies .[92,93]
Bad breast cancer prognosis is positively associated with
high serum IGF-1 concentration in women under hormonal therapy,[94]
while other study
suggest that high serum IGF-1 is associated with increased all-cause mortality in women
with breast cancer.[95]
Komen.[15]
reported a summary table of 13 nested case control studies with at least 300 breast
cancer and pooled analysis that estimate the risk of IGF-1 for breast cancer. In premeopausal
women 7 from 10 studies indicated a relative risk of 1.09 to 2.88, while in postmeopausal
women 8 from 11 show a relative risk of 1.0 to 1.59. Our study indicated that 36% of women
with breast cancer are with IGFserum level lower than lower cut-off serum value, while in
controls the corresponding value for controls was 2%. In addition, in both control and breast
cancer groups none of them show serum IGF value of higher than the high limit cut-off value.
Although of such diversity in findings regarding the serum concentration of IGF-1 in women
with breast cancer.[96]
It was hypothesized that inhibition of IGF-1 action might be alternative and better to blocking
estrogene action in prevention of breast cancer development.[97]
Patient age seems to
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influence IGF-1 serum concentration as this study indicated that it was higher in
premenopausal than in postm enopausal women. This finding agreed to that reposted by
others.[82]
Although there is an association between circulating IGF-1 and type 2 diabetes, the
influence of diabetes on its concentration still unclear.[96]
Reported studies indicated that
circulating IGF-1 either increased, decreased or not chaged in diabetes patients [98-103] and
IGF-1 receptor expression in breast tissue was similar among diabetic patients and control.[99]
IGF-1 system enhancement in breast carcinogesis among diabetes patients may be mediated
more likely through the activation of IGF-1signaling pathway via a high concentration of
insulin through cross-activation of IGF-1R and therefore modified cell growth, differentiation
and transformation, and cancer development.[80,96,104-107]
Studies in animal models and in vitro suggested tha anti-proliferative effect of Vit D on
breast cancer cells.[108]
Geographical difference in incidence of breast cancer may illustrate
the beneficial effect of vitamin D levels which differ due to solar exposure.[109-111]
Other
studies suggest better survival in breast cancer patients during summer and autumn.[112,113]
Epidemiological studies that investigate the incidence of breast cancer association with vit D
are with conflicting results.[32, 108, 114,115]
Rose et al.[2013]
meta-analysis reported an association
between poor survival and low concentration of vit D.[116]
The present study indicated that
women with breast cancer were with significant lower mean serum level of vit D as
compared to controls, with an odd ratio of 4310 between reduced serum level and breast
cancer. Only 4% of our breast cancer cohort are with vitamin D serum levels above the low
cut-off level, while all control subjects are with cut-off of above 10.
Inverse correlation between low pre-diagnostic levels of vitamin D and high breast cancer
mortalit.[117]
In contrast to the periously reported inverse correlation between levels of PTH
and vitamin D.[118]
the present study found that both are reduced in women with breast
cancer. However, calcium mean serum oncentration was higher in breast cancer than in
control and 95% of patient are with serum levels higher than cut-off value. Thus, this may
explain why our breast cancer cohort are with low levels of PTH since this hormone is
secreted from the parathyroid gland when calcium levels are low and stimulates release of
calcium from bone into blood. Reported studies suggest that PTH is with cancer promoting
effect and carcinogenic effect.[119-122]
and hyperparathyroidism may be a risk for breast cancer
development.[123-126]
Huss et al.[127]
not found an association between pre-diagnostic levels of
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Abdulghani et al. World Journal of Pharmacy and Pharmaceutical Sciences
PTH and breast cancer survival. AUC of ROC indicated a highly significant association
between breast cancer and decreased circulating PTH and vitamin D in our cohort study.
Pre-diagnostic calcium levels high levels associated with increased incidence of breast
cancer[128]
and pstients survival [127]
The conflicting results concerning the risk of vit D, PTH
and calcium in breast cancer may be due to methodology used in different studies, the study
design and geographical variation.[127,129-144]
In conclusion, this study indicated a significant association between breast cancer and serum
levels of prolactin, progesterone, estrogene, progesterone receptor, estrogene receptor, sugar,
HBA1C, insuline growth factor , Ca+2
, Vit. D and PTH. However, AUC of ROC indicated
the low predictive value of estrogene and progesterone.
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