bio markers in women with breast cancer: ii

www.wjpps.com Vol 4, Issue 07, 2015.

74

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


75


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.


76


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


77


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).


78


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]


P value <0.0001 <0.0001


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]


P value <0.0001 <0.0001


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


80


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]


P value <0.0001 <0.0001


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]


P value <0.0001 <0.0001


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]


P value <0.0001 <0.0001

Relative risk 18 3.48


81


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]


P value <0.0001 <0.0001


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]


P value <0.0001 <0.0001


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]


P value <0.0001 <0.0001



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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


83


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]


84


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


85


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


86


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


87


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


88


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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