Introduction

Breast cancer (BC) is the most significant common cancer identified among women in developed countries. It is the second foremost cause of cancer death among women after lung cancer (Allemani et al., 2015). The category of breast carcinoma depends on clinicopathological features and the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Though great progressions in cancer diagnosis and treatment lately, BC remains, a primary reason for death for a woman (Lohman, Roche, & Martorell, 1988; Maclean et al., 2015).

It has consistently revealed that the risk for numerous cancer types comprising that of the liver, pancreas, colorectal, and breast is higher in insulin-resistant patients (Cowey & Hardy, 2006). Insulin improves the bioactivity of insulin-like growth factor-1 (IGF-1) (Rose, Komninou, & Stephenson, 2004). Also, the bioactivity and bioavailability of IGF-1 are affected by six binding proteins (IGF-binding proteins (IGFBPs) that also exert independent biological actions (Pollak, 2008). The IGFBP-1 has stimulatory and inhibitory influences on IGF-1 bioactivity, with the phosphorylated form of IGFBP-1 inhibiting IGF-1 system, whereas the unphosphorylated form has a stimulatory impact. Adipocyte secretion of IGF-1 has been established to directly stimulate BC cell proliferation in vitro (Lubik et al., 2013).

Obesity, as a chief health problem, is connected with increased BC occurrence and consequent mortality. The particular mechanism linking obesity and BC risk remains uncertain. Still, it has been proposed that adipose tissue can produce a group of cytokines counting leptin and adiponectin, which may trigger such relationship and play as prospective biomarkers and treatment targets for the management of this destructive disease (Dossus et al., 2017).

Leptin is a 16 KDa neuroendocrine hormone that acts as a multifunctional protein with 167 amino acids, formed primarily by white adipose tissue. There is negligible leptin production in normal circumstances which increases in particular pathological processes such as inflammation and malignant alterations (Polyzos & Mantzoros, 2015).

Adiponectin is a 247 amino acid. It is a protein hormone that modulates several metabolic processes, comprising glucose regulation and fatty acid oxidation. Adiponectin is secreted from adipose tissue. It has found that adiponectin inversely interrelated with body mass index (BMI) in patients (Ahlstrom et al., 2017).

Resistin is a 12.5 kDa protein secreted by adipocytes, macrophages, and bone marrow cells has been initially concerned in the pathogenesis of obesity-mediated IR, also has been studied expansively for its role in inflammation and obesity-related cancers (Gong et al., 2016). Resistin has been proposed to be an inflammatory marker in humans because macrophages are well-known inflammatory modulators. It was found that resistin favours the transformation of macrophage into foam cells by de restricting cell receptors, a phenomenon that leads to lipid accumulations and alteration in endothelial effective, which may represent the significant problematic event associated with atherosclerosis (Jamaluddin, Weakley, Yao, & Chen, 2012). Therefore, the target of this work is to estimate the circulating levels of IGF-1, leptin, adiponectin, and resistin among premenopausal Iraqi women with BC.

Patients and Methods

The current work was performed during the period from June 2019 to December 2019 at Oncology unit/ Medical City Hospital- Baghdad. A total of 90 premenopausal women with BC/ stage II and III after 2^nd dose of chemotherapy were included in this study as patients group. Their ages ranged from (35-50) years in addition to 90 premenopausal healthy women were selected according to the normal mammographic outcomes and no history of cancer as a control group.

Additionally, women with BC were categorized according to BMI into two groups: obese (n= 48) and overweight (n= 42). Also, they were categorized according to: the tumors size 2-5 cm (n= 55) or > 5 cm (n= 35).

The study was permitted by an institutional ethics committee of the Iraqi Ministry of Health and Medical City Hospital/ Baghdad, and the procedures followed were in accordance with the applied guidelines. Clinical and pathological information. Weight and height for every subject were also recorded, date and type of treatment, tumour grade, as well as immuno-histochemical evaluation of ER and PR status, obtained from medical records.

Clinicopathologic Characteristics of Tumor

The status of ER and PR were examined by immunohistochemical staining (DAKO, USA).

Measurements

Blood pressures were recorded according to the guidelines adopted by the WHO. The BMI and waist circumference (WC) were determined for patients and controls (Dubois, Delort, Billard, Vasson, & Caldefie-Chezet, 2013).

Blood glucose and serum lipid profile encompassing: [total cholesterol (TC), triacylglycerol (TAG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)] were determined using Hitachi auto-analyzer. Serum IGF-1 concentration was determined by IRMA-Immunotech kit, France. While, serum CA15-3 concentration was determined using Monobind equipment, USA (Martinetti et al., 2014).

Serum leptin, adiponectin, and resistin were determined using the microplate-ELISA bioassay system as formerly stated (Torre et al., 2015) by (Bio-Rad Laboratories, Inc., Berkeley, CA, USA).

Statistical Analysis

All data are shown as means ± SD for all parameters. The t-test was used to equate experimental groups. Also, p-value ≤ 0.05 was deliberated statistically substantial

Results

Clinicopathological characteristics in BC patients included: histological stage, tumor size, lymph node metastasis, hormonal receptor positive, and duration of the disease were illustrated in Table 1.

There was no substantial variance in age between the two groups. While, there was a considerable increase (p ≤ 0.05) in WC, BMI, SBP, and DBP in BC group as compared to the healthy group, Table 2.

Also, there was a significant increase (p ≤ 0.05) in FSG, serum TC, TAG, LDL-C, CA15-3, IGF-1, leptin, leptin/adiponectin (L/A) ratio, and resistin. While there was a substantial decrease in serum adiponectin (p= 0.01) in patients as paralleled to healthy, as shown in Table 2.

There was a substantial rise (p ≤ 0.05) in serum IGF-1, leptin, and resistin in obese patients as paralleled to overweight. While there was a reduced in serum adiponectin in obese patients as paralleled to overweight, but it was not significant. Moreover, there was an elevation in L/A ratio in obese patients, but it was not substantial Table 3.

Additionally, circulating levels of serum IGF-1, leptin, and resistin were significantly increased (p= 0.001) among patients who had tumour size > 5 cm paralleled to those with tumour size 2-5 cm. Also, the ratio of L/A was elevated in cases with tumour size > 5 cm. Though, there was a reduction in serum adiponectin in those patients as compared to patients with tumour size 2-5 cm, Table 4.

Furthermore, correlation coefficients (r) between serum IGF-1 and adipokines in BC patients are shown in Table 5. There were significant positive correlations between serum IGF-1 and serum leptin, L/A ratio, and resistin in BC patients. At the same time, there was a substantial negative association with serum adiponectin in BC patients.

Discussion

Breast cancer is the most commonly identified cancer in Arab women (Ewertz et al., 2012). It has been examined an association between diverse cancer subtypes and anthropometric measures of obesity (Ma et al., 2013). It has been documented that obesity-associated BC is more frequently ER+ than is the overall case (Chang et al., 2016).

Nevertheless, relations between BMI and premenopausal BC were less reliable. A diffident common of revisions reported that premenopausal obesity is inversely associated with BC risk and proposed a defensive influence (Azoulay, Soldera, Yin, & Bouganim, 2016).

Results in the current study revealed that BMI is related to progressive stage and grade of breast carcinoma among female patients. These outcomes further funding existing evidence of a greater effect of obesity. Thus, high central obesity may reveal low fitness and low-grade inflammation, which are both related to an elevated risk of cancer (Garg, Maurer, Reed, & Selagamsetty, 2014). Epidemiological and clinical evidence proposed that obesity is linked with a higher risk of BC and resistance to BC treatment. It has been suggested that this positive relationship may be confounded by BMI of 25 kg/m² at least (Dubois et al., 2013).

Ewertz and colleagues, 2012 determined that the risk of increasing metastasis in early-stage of obese patients increased by 42-46% after ten years, paralleled to overweight patients, and the risk of death due to BC after 30 years was considerably increased by 38% in obese patients. A Women’s Health Initiative trial revealed that BMI related to a higher risk of ER+ and PR+ among BC patients (Neuhouser et al., 2015).

As one constituent of metabolic syndrome, hypertension was described to connect with improved BC risk in a meta-analysis, with the pooled risk estimates that was comparable to the present result. Nevertheless, this relationship is composite, and it is still uncertain whether it is causal, as both hypertension and cancer are exaggerated by parallel risk influences such as obesity, smoking, alcohol consumption and physical inactivity (Koene, Prizment, Blaes, & Konety, 2016).

Numerous mechanisms have been suggested for an association between hypertension and BC risk. First, both factors may share corporate pathophysiological pathway intermediated by adipose tissue, which could cause chronic inflammation and improved the risk of both BC and hypertension. Additional potential clarification that is hypertension may rise BC risk by obstructing and consequently modifying apoptosis, thus disturbing the regulation of cell turnover.Finally, another study revealed women who used antihypertensive medications exhibited an improved chance of BC paralleled to those without antihypertensive drugs. This may be due to the use of calcium channel blockers was related to an over two-fold improved of BC risk (Largent et al., 2006).

Additionally, the previous study has shown that high glucose can provide the optimal growth environment for tumours (Elgendy et al., 2019).

(Sun, Sun, Rong, & Bai, 2019) data proposed that high glucose-stimulated cell proliferation, capability, and anchorage-independent growth, which indicated that high glucose donated to the metastatic behaviour of BC as well. Obesity has influences on a number of hormones and growth factors possibly connected to BC. A significant collection of obesity-associated metabolic concerns comprise different concentrations of circulating adipocytokines and progress of insulin resistance (IR) comprising hyperinsulinemia and impaired glucose metabolism (Dumais et al., 2017).

As LDL and HDL mostly transport cholesterol, these lipids have linked them with BC. It has found that LDL-C level greater than 117 mg/dl is a prognostic influence of tumour stage, also, related with poorer prognosis due to a greater histological grade, higher proliferative rate, and more progressive clinical stage. Furthermore, patients who have LDL-C greater than 144 mg/dl were also prone to have lymph node metastasis (Santos, Fonseca, Dias, & Almeida, 2014). Further significantly, other studies propose that genetically higher LDL-C was related to a greater of BC risk (Nowak & Ärnlöv, 2018).

In the present study, it was observed that a significant increase in serum CA15-3 in the comparison between the control group and all patients group. This result is in harmony with that reported by (Khan, Trivedi, & Atara, 2016), who found that an increase in serum CA 15-3 concentrations in BC patients paralleled to the control group. These results are in covenant with the current study.

The IGF-1 is an effective growth factor with a role in cancer pathogenesis, which has been associated in epidemiological revisions to cancer. Moreover, it can rise normal cell cycling, leading to improved risk of mutation and malignant transformation. One probable mechanism clarifying the relationship between obesity and cancer other than estrogen is IR. Insulin improves the activity of IGF-1, and high circulating of IGF-1 levels are interrelated with the risk of BC progress. Thus, higher levels of IGF-1 have been associated with cancer death (Shanmugalingam, Bosco, Ridley, & Hemelrijck, 2016).

Cumulative revisions have specified that adipokines, complicated in the mediation of inflammatory diseases and obesity (Akter, Faruque, & Nahar, 2019; Deshmukh et al., 2017), which are in agreement with the present study.

Adipokines, predominantly leptin, may have a chief role in BC biology. Obesity is related to high levels of leptin. Obesity is accompanied by leptin resistance. It has been firmly that BC related to obesity and hyperleptinemia, also with immunological investigation conflicts. This complex network proposes crosstalk among leptin, immune response and development of BC in obese women (Reilly et al., 2005).

Furthermore, adiponectin is convoluted in the reduction of tumour size in animals and declined serum adiponectin concentrations are related to the progression of BC among women. Metabolic dysregulations linked with obesity such as hyperleptinemia and hypoadiponectomia are probable to stimulate cancer cell growth via particular mechanisms. When mammary cells are involved in the process of carcinogenesis, they produce adipokines mostly leptin capable of acting on surrounding cancer cells in an autocrine and paracrine manner (Shacter & Weitzman, 2002).

It has been hypothesized that the L/A ratio could be more convenient as a biomarker because both hormones involved in this formula are aggressive in their final result on tumourigenesis (Santillán-Benítez et al., 2013). Therefore, this variable could designate that metabolic regulation has protective elements against the higher leptin levels.

The current study revealed an elevation in this ratio. So, it could be possible to decrease this ratio by modifying the patient's diet and lifestyle, which would alter the vulnerability to cancer through the inhibition of the leptin pathway. Regarding the CA15-3 level, it appears that obese patients are more susceptible to elevated levels of this marker irrespective of the cancer diagnosis.

Numerous adipokines have been implied in cancer progress, primarily through IR and inflammation. An elevated level of most of these adipokines such as leptin and resistin has shown a pro-carcinogenic role. The present study showed that BC patients had considerable levels of serum resistin than the healthy group.

High levels of resistin have been reported in some forms of malignancies, including (Fasshauer & Blüher, 2015). Additionally, the levels of resistin with breast tumour size, stage and lymph node metastasis. It has been conducted that increased concentrations of resistin were connected with increases in BC risk (Liu et al., 2017).

Serum resistin is consistently correlated with cancer development, including BC. It has also been recommended that the expression of resistin in cancer cells is related to more malignant clinical and pathological processes (Cormanique et al., 2015).

The outcomes of this study indicated that BC patients showed significantly higher mean value of serum resistin than the control group.

Because the earlier revisions documented that resistin is expressed from adipose tissue and also from monocytes and macrophages, and associated with specific inflammatory markers directly, the role of resistin as a further marker of inflammation has traditional growing concern (Yang et al., 2016). Inflammation may be characterized by biomarkers of primary pathologic modifications in breast cells and be related to risk for the BC progress. Consequently, an association between serum resistin concentrations and BC risk might be partially clarified by inflammation (Assiri & Kamel, 2016).

Conclusion

Serum IGF-1, adiponectin, and L/A ratio may have a relationship with invasiveness and metastasis of BC. Both high serum leptin and resistin concentrations are probably to be related to improved BC risk among Iraqi women. Clinical and pathological features of the tumour recommended that these adipokines might affect the development of BC. Thus, adipokines in complex and interrelated mechanisms may be drive BC initiation and progression.

Funding support

None

Conflict of interest

The author declares that there is no conflict of interest.