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Association of Serum Adiponectin and Leptin Levels with Breast Cancer in Iraqi Women

Dhuha F. Taaban*, Eman S. Saleh, Zainab M. Hashim, Zuhair B. Kamal

Department of Clinical laboratory sciences, College of Pharmacy, University of Baghdad, Baghdad, Iraq

Abstract: Obesity has been associated with an increased risk of cancer especially postmenopausal breast cancer. Adipokines have been hypothesized to underlie this association. Adiponectin and leptin are adipocyte-secreted hormones that opposite each other not only in their biological activities but also in their effects on breast neoplastic cells. in addition, Leptin receptor, found in both membrane-bound isoforms and a soluble form (sOB-R), sOB-R bind to leptin in circulation and correlate with its activity. The aim of this study was to investigate the relationship between serum levels of adiponectin, leptin and sOB-R with breast cancer. Methods: In a case-control study Serum adiponectin, leptin and sOB-R levels were measured by enzyme-linked Immunosorbent assay in 48 women with histologically confirmed breast cancer and compared with 41 age and BMI matched women without breast cancer as control groups. Control groups were divided into; Control group 1 (C1) contains 26 healthy women and control group 2(C2) contains 15 women with breast benign diseases. Results: The mean serum levels of adiponectin in both controls (C1 and C2) were signiﬁcantly higher than that in breast cancer cases (25.08±5.59and 22.49±3.49) versus (15.84±6.21) respectively. Conversely, the mean serum levels of leptin in both controls (C1 and C2) were signiﬁcantly lower than that in breast cancer cases (27.98±6.85 and 34.50±10.59) versus (48.97±24.56) respectively. Higher circulating levels of sOB-R (140.21±74.20) were significantly associated with an increased risk of breast cancer as compared to controls (47.13±38.30 and 27.68±23.58) for C1 and C2 respectively. In addition, the association of BMI with breast cancer was non-significant. Conclusion: These data suggest that dysregulation in hormones (adipokines) secreted by adipose tissue may be associated with breast cancer independently of BMI. Further prospective studies examining the role of adipokines in the etiology of breast cancer are warranted.

Keywords: breast cancer, obesity, adiponectin, leptin, soluble leptin receptor

Received September 27, 2014; Revised December 05, 2014; Accepted December 15, 2014

Citation: Dhuha F. Taaban, Eman S. Saleh, Zainab M. Hashim, Zuhair B. Kamal, Association of Serum Adiponectin and Leptin Levels with Breast Cancer in Iraqi Women. American Journal of Pharmacological Sciences, 2 (6). 103-109. January 2014. doi:10.12691/ajps-2-6-2

1. Introduction

Breast cancer (BC) is the most common cancer in women worldwide [1]. According to the latest Iraqi Cancer Registry, BC is the commonest type of female malignancy, accounting for approximately one-third of the registered female cancers [2].

Obesity has been consistently associated with an increased risk of postmenopausal BC; in addition, obesity in women diagnosed with BC is associated with greater tumor burden and with higher-grade tumors lead to overall poorer prognosis and/or increased mortality for both premenopausal and postmenopausal women [3,4,5,6]. In Iraq, a survey held by the Ministry of Health reported that the prevalence of overweigh and obesity (47%-67%) among females and males respectively [7]. Another study carried out in Basrah over the period from May 2003 to April 2010 found that; obesity and overweight was seen in 55.1% of population (54.7% women, 45.3 % men), prevalence of overweight alone was 31.3% (50.2% men and 30.9% women) and obesity was 23.8% (61.1% of women, 18.6% men), Obesity was more prevalent in women than in man [8].

The implications of obesity and cancer association for cancer prevention and the hormonal mechanisms by which obesity may affect BC risk are not fully understood. Several possible mechanisms for this association have been hypothesized, including increased estrogen production in non-ovarian tissues, increased insulin and IGF and changes in circulating adipokines concentrations [9,10,11].

Adipocytes within a context of obesity, by the action of “adipokines”, participate in a highly complex cross talk with tumour cells to promote tumour progression [12]. Animal studies, microarray analysis, and in vitro tumor studies provide evidence that adipose tissue and these adipokines can directly influence tumor growth [13,14]. Some of the most compelling evidence comes from a study demonstrate that, tumors formed from human BC cells injected into adipocytes of mice grew three times larger than tumors from human BC cells injected into the fibroblasts of mice [14].

Two adipokines, leptin (Lp) and adiponectin (ApN) have been studied for their inﬂuence on the BC risk and tumour biology, their biological activities as their effects on breast neoplastic cells are largely in opposition to each other [12], for this reason, the two adipocytokines are combined to calculate the Lp: ApN ratio. It was observed that people with an increased Lp: ApN ratio have a higher risk developing BC [15]. The higher the Lp: ApN ratio the greater is the tumor size, indicating a positive correlation [10].

Adiponectin (ApN) has in contrast to Leptin, anti-diabetic, anti-inflammatory, anti- atherogenetic effects as well as anti-neoplastic effect [16]. ApN level and body mass index are inversely correlated. normal weight people have a physiologically increased serum ApN level in contrast, in obese individuals ApN biosynthesis is down regulated, which leads to hypoadiponectinemia, not only BMI, but also the risk for BC is inversely correlated with ApN level in serum [17,18].

Leptin is an anorexigenic peptide that plays a key role in energy homeostasis and appetite control [19]. In addition, Leptin has been shown to have mitogenic effects on epithelial cells and to promote cellular proliferation, migration, and invasion in breast cancer cell lines [20,21]. In humans, the circulating Lp level is increased in obesity, suggesting that a hallmark of obesity is not Lp deﬁciency, but Lp resistance [22,23].

Lp exerts its pleiotropic actions directly through distinct receptors (ob-R) encoded by the diabetes (db) gene and was identified as a member of the cytokine family of receptors, The Lp receptor gene was found to encode at least ﬁve alternatively spliced forms, ob-Ra, ob-Rb, ob-Rc, ob-Rd, and ob-Re [22,24]. Besides membrane-bound isoforms of the Lp receptor with varying cytoplasmic length, a soluble form of the Lp receptor (sOB-R) has been demonstrated [25]. sOB-R, a special Lp receptor with the extracellular domain only, is formed by ectodomain shedding of Lp receptors on the cell surface [25]. Lammert et al. observed that Lp-binding activity was correlated with levels of the sOB-R and that sOB-R was the major Lp-binding protein in the circulating human blood [26]. The function of sOB-R is not entirely clear but believed to delay the clearance of Lp from the circulation and, thus, increase its availability [27]. In addition, there is evidence suggesting that sOB-R not only alters the clearance of Lp but also potentiates Lp action [28].

2. Subjects and Methods

2.1. Subjects

This case –control study consists of three groups. First group was composed of 48 unrelated women with histopathologically conﬁrmed breast cancer that had not undergone any previous treatment. In addition to two control groups that include; 26 apparently healthy women as control group 1(C1) and 15 women with breast benign (fibroadenoma) as control group 2 (C2), the diagnosis of fibroadenoma was conﬁrmed by both mammography and/or histopathology analyses, both matched for BMI and age of breast cancer patient and without any personal history of breast cancer or other malignancies. Control subjects were selected randomly among women admitted to the Women's Health Center for early detection of breast cancer/ Baghdad during the same period. All patients and subjects enrolled in the study informed about the study and consent was taken. The study was approved by the Clinical Research Ethics Committee of Pharmacy College University of Baghdad.

Clinical information was obtained from the hospital record for all patients. The dataset contains information on the following: Type of cancer, Age and menopausal status at diagnosis, body mass index, Chemotherapy status, hormonal receptor status (estrogen receptor, progesterone receptor), Tumor type, size, grade and Lymph Node Status.

All Participants completed interview-administered questionnaires regarding demographic and behavioral factors, including smoking history, recreational physical activity, medical, reproductive, and family history. Subjects with a history of smoking, previous cancer and endocrine-related illnesses or had taken exogenous hormones in the three months preceding blood collection were excluded from the study.

2.2. Measurements

Body mass index was calculated as body weight (in kg) divided by square height (m²). all the participant were measured by standard methods, while they wearing light clothing and not wearing shoes. Waist and hip circumference was determined by measuring tap with cm scale. Waist to hip ratio (WHR) determined by dividing waist circumference (in cm) on hip circumference (in cm) [29].

2.3. Laboratory Evaluation

Specialized laboratory staff who did not participate in the study did Blood specimen collection from each woman. A volume of 5 mL of blood samples were collected into gel-containing tubes and Sera were obtained by processing of clotting and centrifugation. The serum samples were stored frozen at −70°C for serum adiponectin, leptin and sOB-R measurement.

Serum adiponectin, leptin and sOB-R concentrations were measured by enzyme-linked immunosorbent assay (ELISA) using a commercially available kits, human adiponectin ELISA kit (CUSABIO®/China, E07270h), human leptin ELISA kit (CUSABIO® / China, E04649h) and human sOB-R ELISA kit (CUSABIO®/China, E04647h) respectively.

The technique used depends on a quantitative Sandwich-Assay using two specific and high affinity antibodies, the microtiter plate provided in the kit has been pre-coated with an antibody specific to substance to measure. Brieﬂy, after dilution according to manufacturing manual samples pipetted into the microtiter plate wells and incubated for 2 hours at 37°C, after removing any unbound substances, a biotin-conjugated polyclonal antibody specific for measured substance is added to the wells and incubated for 1 hour at 37°C. After washing, strepto-avidin conjugated to Horseradish Peroxidase (HRP) is added to each microplate well and incubated again for 1 hour at 37°C. Following a wash to remove any unbound avidin-enzyme reagent, a TMB (3, 3’5, 5' tetra methyl-benzidine) substrate solution is added to the wells and color develops in proportion to the amount of substance bound in the initial step. The enzyme-substrate reaction is terminated by the addition of sulphuric acid solution and the color change is measured spectrophotometrically at a wavelength of 450 nm [26,30,31].

2.4. Statistical Analysis

Statistical software (SPSS version 21, Chicago, IL, USA) was used for data input and analysis. Continuous variables were presented as mean ± standard deviation of mean (SD). One-way analysis of variance (ANOVA) was used to examine the degree of difference among studied groups, followed by Fisher least significant difference (LSD) to identify significantly different means. Pearson’s correlation coefficient (r) was used to test the statistical correlations between studied parameters. The association between breast cancer and serum levels of adiponectin, leptin, sOB-R, Lp/ApN ratio, Lp/sOBR ratio, and anthropometric measurements were determined as ORs and 95% CIs according to the conditional logistic regression analysis. In all data present in this study, findings with P value less than 0.05 were considered statically significant.

3. Results

3.1. Baseline Characteristics

Table 1 represents mean ± standard deviation (SD) for age, anthropometric variables, adiponectin, leptin, Lp/ApN ratio,sOB-R and leptin/sOB-R ratio.

Table 1. Mean±SD for age, anthropometric, ApN, Lp, Lp/ApN, sOB-R, and Lp/ sOB-R in the studied groups

As summarized in Table 1, the results of the study showed no significant difference (P > 0.05) regarding the mean age ± SD between BC group (50.4±12.2) and the healthy (C1) controls (47±10.28), however, the breast benign group (C2) have significantly different mean age (36.6±8.33), (p<0.001) as compared to BC group. BMI was comparable in all three groups, however; WHR was significantly higher in BC group (p<0.01) as compared to C1 and C2 groups.

Adiponectin was significantly lower in BC cases compared with the controls (P< 0.001), Leptin was significantly higher in BC as compared to C1 and C2 groups (p< 0.001, p< 0.02) respectively, Lp /ApN ratio and sOB-R levels were significantly higher in breast cancer cases when compared with C1 and C2 groups (P< 0.001). Contrary, Leptin/sOB-R ratio was significantly lower in breast cancer cases compared with the C1 and C2 (P< 0.05, P< 0.02) respectively.

3.2. Correlations Studies

3.2.1. Correlation between Adiponectin, Leptin, Soluble Leptin Receptor and Anthropometric among All Studied Groups Combined

Table 2. Correlations between adiponectin, leptin, Lp/ApN ratio, sOBR, Lp/sOBR ratio and anthropometric

As shown in Table 2, when the whole study subjects was analyzed, the serum adiponectin level was negatively correlated with Lp/ApN ratio and sOB-R level (P< 0.01),this was in contrast to leptin which correlated positively with Lp/ApN ratio and sOBR(P <0.01). In addition, leptin and Lp/ApN ratio also correlated positively with both BMI and WHR (P< 0.01) while Lp/sOBR ratio correlated positively with BMI (P< 0.05). sOB-R correlated positively with WHR and Lp/ApN ratio (P< 0.05 and P< 0.01, respectively) while there was a negative correlation between sOB-R and Lp/sOB-R ratio (P< 0.01).

3.2.2. Association of Adiponectin, Leptin and Soluble Leptin Receptor and Breast Cancer

Conditional logistic regression models were used to investigate the association between the risk of breast cancer and the markers measured in the study. Results revealed that the high serum level of leptin (OR =1.098, 95% CI= [1.033-1.168]; P < 0.01), sOB-R (OR =1.024, 95% CI= [1.009-1.040]; P < 0.01) were associated with breast cancer. An inverse association between serum level of adiponectin and breast cancer was observed (OR =0.0791, 95% CI= [0.693-0.903]; P < 0.01 as showed in Table 3. There were no signiﬁcant association between any of the other variables including age, BMI, WHR, Lp/ApN ratio and Leptin/sOB-R ratio and breast cancer.

Table 3. Association of serum levels of adiponectin, leptin and soluble leptin receptor and breast cancer based on a case and control analysis

4. Discussion

As obesity has been associated with the development of breast cancer, adipocytokines, a group of polypeptide growth factors and cytokines, which are produced exclusively by adipose tissue, such as adiponectin and leptin, may underlie the association between obesity and breast cancer risk [10].

In this study, we found that the serum levels of leptin, soluble leptin receptor and Lp/ApN ratio were signiﬁcantly higher in breast cancer patients than controls. Contrary significantly lower serum levels of adiponectin and Lp/sOBR ratio were found in breast cancer cases than control subjects. Rrelationships were demonstrated between serum levels of leptin, Lp/ApN and Lp/sOBR ratio with BMI. In addition, serum levels of ApN, Lp, Lp/ApN ratio, Lp/sOBR ratio and WHR ratio were correlated with sOB-R serum levels as shown in Table 2. There was non-significant difference regarding the mean age of BC cases and the first control group, healthy control (C1); however, the difference was significant as compared to the second control, breast benign control (C2), since benign breast diseases usually more common among younger age women.

Adiponectin serum levels decrease with increasing body fatness while leptin levels increase. Functionally, they appear to oppose each other's actions. In addition, sOB-R, although the function of sOB-R is not entirely clear, but believed to modulate leptin effect by increasing its availability [27]. Moreover, there is evidence suggesting that sOB-R can also potentiates leptin action [28]. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. The role of these adipocytokines, adiponectin and leptin, in addition to sOBR in Iraqi breast cancer patients remains to be determined. It is possible that the levels of adiponectin and leptin receptors, as well as the balance of serum adiponectin and leptin, are critical factors in mammary tumorigenesis.

The result of the current study suggest that serum adiponectin levels are inversely associated with breast cancer; this was consistent with many other studies [32]-[36]. Miyoshi et al [32] was the first to found a strong inverse association between adiponectin and breast cancer risk among both pre- and post-menopausal women. This was supported by other studies [35,36]. However, other groups reported that low adiponectin levels are associated with breast cancer only in post-menopausal women [33,34,37]. Adiponectin concentration has a significant negative correlation with estradiol in postmenopausal but not in premenopausal women [38]. That might help to explicate the divergence, but the mechanism of adiponectin on postmenopausal women and premenopausal women still need to be discussed.

One possible mechanism explaining associations between obesity and cancer other than estrogen is hyperinsulinemia or insulin resistance. It has been noted that adiponectin stimulates the sensitivity of peripheral tissue to insulin; decreased levels of adiponectin are associated with increased serum insulin levels, which accompany insulin resistance [39]. Insulin enhances the activity of insulin-like growth factor-1 (IGF-1), and high levels of circulating IGF-1 are correlated with risk of development of breast cancer [40]. However, Mantzoros et al [33] reported that associations between serum adiponectin and breast cancer risk were independent of possible effects of major components of the IGF system, leptin, and body mass index.

Adiponectin can blocks proliferation of BC cells [41]. In vitro assays have shown that a number of different BC cell lines express one or both of the ApN receptors and show reduced growth and/or increased apoptosis in response to ApN [42]. Furthermore, the low serum adiponectin levels were found to be significantly associated with large tumor size (>2 cm) and high histological grade (2+3), indicating that tumors with high proliferation activity are more likely to develop under the low adiponectin condition [32]. It is well established that obesity is associated with poor prognosis [3,4,5,6]. This association might be partly explained by the low serum adiponectin levels seen in obese breast cancer patients.

Our study was conducted among 48 breast cancer patients, 26 healthy controls and 15 breast benign controls, The result of our study suggest that the circulating leptin level varies among these different population groups from low to high: healthy people<breast benign diseases patients<breast cancer patients. This observation was consistent with a recent meta-analysis that included 23 studies (2058 breast cancer patients, 2078 healthy controls and 285 breast benign controls ) suggests that leptin might play a role in the formation and development of breast carcinoma and has potential for development as a diagnostic tool [43].

The association of higher serum levels of leptin with BC risk were concordant with the ﬁndings of many other studies [44,45,46]. Llanos et al [47] and Macciò et al [48] have reported that leptin increased risk for breast cancer in postmenopausal women, but had no relationship with onset of premenopausal breast cancer.

Findings of several studies indicate that leptin is involved with diﬀerent aspects of tumor pathology such as cell growth, angiogenesis and metastasis [49,50,51]. Ishikawa et al [52] showed that, leptin might play a role in the carcinogenesis and metastasis of breast cancer, possibly in an autocrine manner. Garofalo et al [53] reported that high leptin level in obese breast cancer patients might contribute to the development of antiestrogen resistance. Animal studies also support a role for leptin in mammary tumor development as evidenced by the fact that mice deficient in leptin Lepob Lepob, or with non-functioning leptin receptors,, Leprdb Leprdb [54], did not develop transgene-induced mammary tumors. Moreover, results from animal studies suggested that leptin receptor antagonists might be a new option for breast cancer treatment [55].

The leptin-mediated proliferation involves a possible interaction between leptin and oestrogen systems to promote breast carcinogenesis [56], as leptin can exhibits oestrogen-producing activity by enhancing aromatase mRNA expression, aromatase protein content and its enzymatic activity and enhances the sensitivity of breast cells to oestrogens via up-regulation of ERα in MCF-7 breast cancer cells [57,58]. In addition, the effect of both leptin and oestradiol on ZR-75 cell proliferation is higher than leptin or oestradiol alone [59]. However, numerous in vitro studies carried out with breast cancer cell lines have found a proliferative effect of leptin in ER-positive cell lines [20,21,60,62], as well as in ER-negative cell lines [49]. These data suggest that leptin-induced cell proliferation cannot be explained only by oestrogen-dependent mechanisms.

In vitro studies also support the role of leptin and leptin receptor in BC cell proliferation [21,63,64]. Dieudonne et al. [21] found that MCF-7 cells expressed leptin receptor and leptin could inﬂuence the growth of human mammary cancer MCF-7 cells. Okumura et al [63] investigated the eﬀects of leptin on the MCF-7 line of human mammary cancer and reported that hyperleptinemia increased breast cancer cell proliferation through accelerated cell cycle progression. On the other hand, Yuan et al [64] have reported that leptin stimulates the growth of breast cancer in the nude mice and promotes the proliferation and migration of MCF-7 human breast cancer cells through the extracellular-signal regulated kinase pathway.

The soluble leptin receptor is involved in modulating leptin activity [26]. In our study we found that high sOB-R levels were strongly associated with a risk of BC, suggesting the overexpression of the leptin receptor in serum could cause an increase of leptin bioactivity or a reduction of leptin clearance due to association with the high molecular binding protein.

Jardé et al [56] had reported signiﬁcant overexpression of leptin and Ob-R in primary and metastatic breast cancer relative to non-cancer tissues, they also observed that leptin positively correlated with Ob-R in primary tumors and that the expression of both proteins was more abundant in high-grade tumors. Garofalo et al [65] found that, 92% of primary breast cancer cases and 83% of lymph node metastasis showed overexpression of leptin and leptin receptor (Ob-R), respectively in breast tumor tissues. This was consistent with the finding of Mahabir et al [23] detected 85% and 75% overexpression of leptin and Ob-R respectively in primary breast cancer cases, with the expression of leptin signiﬁcantly correlated with that of Ob-R. In addition, Ob-R expression in cancer tissue was positively correlated with ER status and tumor size.

Magni et al [66] reported that the ratio of circulating leptin to sOB-R was strongly related to the percentage of body fat. In this study, the leptin/sOB-R ratio was signiﬁcantly lower in breast cancer cases and it was positively correlated with BMI. Moreover, sOB-R rather than leptin/sOB-R ratio was positively correlated with WHR, leptin and Lp/ApN and negatively correlated with adiponectin and Lp/sOB-R ratio levels. This may indicate an interplay between dysregulated adipocytokines level and their receptors as response to central adiposity.

To the best of our knowledge, ours is the ﬁrst study to provide information about the association of serum levels of adiponectin, leptin and sOB-R with breast cancer cases in a sample of Iraqi subjects. Due to the limitations inherent in a case–control study and low sample size, this study cannot elucidate the mechanism or determine the direction of causality, further prospective studies with larger sample size are necessary to clarify the impact of these biomarkers on breast cancer risk.

5. Conclusion

High serum level of leptin and soluble leptin receptor and Low serum level of adiponectin were associated with the breast cancer independent of BMI in a sample of Iraqi population.

References

[1]   | Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11. Lyon, France: International Agency for Research on Cancer; 2013.
[2]   | Iraqi Cancer Board. Results of the Iraqi Cancer Registry 2010. Baghdad, Iraqi Cancer Registry Center, Ministry of Health.
[3]   | Cheraghi Z, Poorolajal J, Hashem T, Esmailnasab N, Doosti Irani A.: Effect of Body Mass Index on Breast Cancer during Premenopausal and Postmenopausal Periods: A Meta-Analysis. PLoS ONE 2012; 7 (12): 51446.
[4]   | Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D. Cancer incidence and mortality in relation to body mass index in the Million Women Study: Cohort study. BMJ 2007; 335: 1134.
[5]   | Cleveland RJ, Eng SM, Abrahamson PE, Britton JA, Teitelbaum SL, Neugut AI, et al. Weight gain prior to diagnosis and survival from breast cancer. Cancer Epidemiol Biomarkers Prev 2007; 16:1803-11.
[6]   | Cleary MP, Grossmann ME, Obesity and Breast Cancer: The Estrogen Connection. Endocrinology. 2009; 150: 2537-42.
[7]   | Iraq Family Health Survey Study Group. Iraq Family Health Survey (IFHS) 2006/7. World Health Organization; 2008.
[8]   | Mansour AA, Al-Maliky AA, Salih M: Population Overweight and Obesity Trends of Eight Years in Basrah, Iraq. Epidemiol 2012; 2: 110.
[9]   | Dalamaga M. Obesity, insulin resistance, adipocytokines and breast cancer: New biomarkers and attractive therapeutic targets. World J Exp Med. 2013 20; 3: 34-42.
[10]   | Vona-Davis L, Rose D P. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Society for Endocrinology. Endocrine-Related Cancer 2007; 14: 189-206.
[11]   | Lorincz AM, Sukumar S, Molecular links between obesity and breast cancer. Endocr Relat Cancer 2006; 13 (2): 279-92.
[12]   | Macciò A, Madeddu C, Obesity, Inﬂammation, and Postmenopausal Breast Cancer: Therapeutic Implications. Scientiﬁc World JOURNAL 2011; 11: 2020-36.
[13]   | Manabe Y, Toda S, Miyazaki K, Sugihara H. Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions. J Pathol. 2003; 201 (2): 221-8.
[14]   | Iyengar P, Combs TP, Shah SJ, Gouon-Evans V, Pollard JW, Albanese C. et al. Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene. 2003; 22 (41): 6408-23.
[15]   | Ray A, Cleary M P. Leptin as a potential therapeutic target for breast cancer prevention and treatment. Expert Opinion Therapy Targets 2010; 14 (4): 443-51.
[16]   | Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: A review of current evidence. Endocr Rev 2012; 33:547-94.
[17]   | Ziemke F, Mantzoros CS. Adiponectin in insulin resistance: Lessons from translational research. Am J Clin Nutr. 2010; 91 (1): 258-61.
[18]   | Van Kruijsdijk R C M, Van der Wall E, Visseren F L J. Obesity and cancer; The role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev. 2009; 18 (10): 1-10.
[19]   | Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763-70.
[20]   | Hu X, Juneja SC, Maihle NJ, Cleary MP. Leptin—a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 2002; 94: 1704-11
[21]   | Dieudonne MN, Machinal-Quelin F, Serazin-Leroy V, Leneveu MC, Pecquery R, Giudicelli Y. Leptin mediates a proliferative response in human MCF7 breast cancer cells. Biochemical & Biophysical Research Communications 2002; 293: 622-8.
[22]   | Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996; 334: 292-5.
[23]   | Mahabir S, Baer D, Johnson LL, Roth M, Campbell W, Clevidence B, et al. Body Mass Index, percent body fat and regional body fat distribution in relation to leptin concentrations in healthy, non-smoking postmenopausal women in a feeding study. Nutr J. 2007; 6: 3.
[24]   | Bornstein SR, Abu-Asab M, Glasow A, Päth G, Hauner H, Tsokos M, et al: Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and diﬀerentiating human adipose cells in primary culture. Diabetes. 2000; 49: 532-8.
[25]   | Ge H, Huang L, Pourbahrami T, Li C :Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo. J Biol Chem 2002; 277: 45898-903.
[26]   | Lammert A, Kiess W, Bottner A, Glasow A, Kratzsch J. Soluble leptin receptor represents the main leptin binding activity in human blood. Biochem Biophys Res Commun 2001; 283: 982-8.
[27]   | Huang L, Wang Z, Li C. Modulation of circulating leptin levels by its soluble receptor. J Biol Chem 2001; 276: 6343-9.
[28]   | Cohen SE, Kokkotou E, Biddinger SB, Kondo T, Gebhardt R, Kratzsch J, Mantzoros CS, Kahn CR. High circulating leptin receptors with normal leptin sensitivity in liver-speciﬁc insulin receptor knock-out (LIRKO) mice. J Biol Chem 2007; 282: 23672-8.
[29]   | Ashwell M, Chinn S, Stalley S, Garrow JS. Female fat distribution a simple classification based on two circumference measurements. Int J Obes 1982; 6: 143-52.
[30]   | Nakano Y1, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a noval gelatin-binding protein purified from human plasma. J Biochem. 1996; 120 (4): 803-12.
[31]   | Imagawa K, Matsumoto Y, Numata Y, Morita A, Kikuoka S, Tamaki M, et al. Development of a sensitive ELISA for human leptin, using monoclonal antibodies. Clin Chem. 1998; 44: 2165-71.
[32]   | Miyoshi Y, Funahashi T, Kihara S, Taguchi T, Tamaki Y, Matsuzawa Y & Noguchi. Association of serum adiponectin levels with breast cancer risk. Clinical Cancer Research 2003; 9: 5699-5704.
[33]   | Mantzoros C, Petridou E, Dessypris N, Chavelas C, Dalamaga M, Alexe DM et al. Adiponectin and breast cancer risk. Journal of Clinical Endocrinology and Metabolism 2004; 89: 1102-1107.
[34]   | Tworoger SS, Heather Eliassen A, Kelesidis T, Colditz GA, Willett WC, Mantzoros CS & Hankinson. Plasma adiponectin concentrations and risk of incident breast cancer. Journal of Clinical Endocrinology and Metabolism 2007; 92: 1510-1516.
[35]   | Kang JH, Yu BY, Youn DS. Relationship of serum adiponectin and resistin levels with breast cancer risk. J Korean Med Sci 2007; 22: 117-121.
[36]   | Macis D, Guerrieri-Gonzaga A, Gandini S. Circulating adiponectin and breast cancer risk: a systematic review and meta-analysis. Int J Epidemiol. 2014; 43 (4): 1226-36.
[37]   | Ye J1, Jia J, Dong S, Zhang C, Yu S, Li L et al. Circulating adiponectin levels and the risk of breast cancer: a meta-analysis Eur J Cancer Prev. 2014; 23 (3): 158-65.
[38]   | Miyatani Y, Yasui T, Uemura H, Yamada M, Matsuzaki T et al. Associations of circulating adiponectin with estradiol and monocyte chemotactic protein-1 in postmenopausal women. Menopause 2008; 15: 536-541.
[39]   | Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 2003; 46: 459-469.
[40]   | Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004; 4: 505-518.
[41]   | Wang Y, Lam JB, Lam KS, et al. Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res 2006; 66: 11462-11470.
[42]   | Dieudonne MN, Bussiere M, Dos Santos E, et al. Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun 2006; 345: 271-279.
[43]   | Niu J, Jiang L, Guo W, Shao L, Liu Y, Wang L. The association between leptin level and breast cancer: A meta-analysis. PLoS One 2013; 8: e67349.
[44]   | Mohammadzadeh G, Ghaffari M, Bafandeh A, Hosseini S. Association of serum soluble leptin receptor and leptin levels with breast cancer. J Res Med Sci 2014; 19: 433-8.
[45]   | Rahmati-Yamchi M, Zarghami N, Rahbani M, Montazeri A. Plasma leptin, hTERT gene expression, and anthropometric measures in obese and non-obese women with breast cancer. Breast Cancer (Auckl) 2011; 5: 27-35.

[46]  
Alokail MS, Al-Daghri N, Abdulkareem A, Draz HM, Yakout SM, Alnaami AM, Sabico S, Alenad AM, Chrousos GP. Metabolic syndrome biomarkers and early breast cancer in Saudi women: evidence for the presence of a systemic stress response and/or a pre-existing metabolic syndrome-related neoplasia risk? BMC Cancer. 2013 Feb 4; 13: 54.

[47]   | Llanos AA, Dumitrescu RG, Marian C, Makambi KH, Spear SL, Kallakury BV, et al. Adipokines in plasma and breast tissues: Associations with breast cancer risk factors. Cancer Epidemiol Biomarkers Prev 2012; 21: 1745-55.
[48]   | Macciò A, Madeddu C, Gramignano G, Mulas C, Floris C, Massa D, et al. Correlation of body mass index and leptin with tumor size and stage of disease in hormone-dependent postmenopausal breast cancer: Preliminary results and therapeutic implications. J Mol Med (Berl) 2010; 88: 677-86.
[49]   | Ray A, Nkhata KJ, Grande JP, Cleary MP. Diet-induced obesity and mammary tumor development in relation to estrogen receptor status. Cancer Le 2007; 253: 291-300.
[50]   | McMurtry V, Simeone AM, Nieves-Alicea R, Tari AM. Leptin utilizes Jun N-terminal kinases to stimulate the invasion of MCF-7 breast cancer cells. Clin Exp Metastasis 2009; 26:197-204.
[51]   | Rene Gonzalez R, Wa ers A, Xu Y, Singh UP, Mann DR, Rueda BR, et al. Leptin-signaling inhibition results in eﬃ cient anti-tumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res 2009; 11:R36.
[52]   | Ishikawa M, Kitayama J, Nagawa H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 2004; 10: 4325-4331.
[53]   | Garofalo C, Sisci D, Surmacz E. Leptin interferes with the effects of the antiestrogen ICI 182,780 in MCF-7 breast cancer cells. Clin Cancer Res 2004; 10: 6466-6475.
[54]   | Cleary MP, Juneja SC, Phillips FC, et al. Leptin receptor-deficient MMTV-204;TGF-alpha/Lepr(db)Lepr(db) female mice do not develop oncogene-induced mammary tumors. Exp Biol Med (Maywood) 2004; 229: 182-193.
[55]   | Otvos L Jr, Kovalszky I, Riolfi M, Ferla R, Olah J, et al. Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer. Eur J Cancer 2011; 47: 1578-1584.
[56]   | Jarde T, Caldeﬁe-Chezet F, Damez M, et al. Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma. Oncol Rep 2008; 19 (4): 905-11.
[57]   | Fusco R, Galgani M, Procaccini C, et al. Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting. Endocr Relat Cancer 2010; 17 (2): 373-82.
[58]   | Catalano S, Marsico S, Giordano C, et al. Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 2003; 278 (31): 28668-76.
[59]   | Chen C, Chang YC, Liu CL, Chang KJ, Guo IC. Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. Breast Cancer Res Treat 2006; 98 (2): 121-32.
[60]   | Jarde T, Caldeﬁe-Chezet F, Goncalves-Mendes N, et al. Involvement of adiponectin and leptin in breast cancer: clinical and in vitro studies. Endocr Relat Cancer 2009; 16 (4): 1197-210.
[61]   | Somasundar P, Yu AK, Vona-Davis L, McFadden DW. Differential effects of leptin on cancer in vitro. J Surg Res 2003; 113 (1): 50-5.
[62]   | Laud K, Gourdou I, Pessemesse L, Peyrat JP, Djiane J. Identiﬁcation of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line. Mol Cell Endocrinol 2002; 188 (1-2): 219-26.
[63]   | Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M, et al. Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: Reciprocal involvement of PKC-alpha and PPAR expression. Biochim Biophys Acta 2002; 1592: 107-16.
[64]   | Yuan HJ, Sun KW, Yu K. Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway. Mol Med Rep 2014; 9: 350-4.
[65]   | Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, et al. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: Possible role of obesity-related stimuli. Clin Cancer Res 2006; 12:1447-53.

[66]  
Magni P, Liuzzi A, Ruscica M, Dozio E, Ferrario S, Bussi I, et al. Free and bound plasma leptin in normal weight and obese men and women: Relationship with body composition, resting energy expenditure, insulin-sensitivity, lipid proﬁ le and macronutrient preference. Clin Endocrinol (Oxf) 2005; 62: 189-96.