DISCUSSION

To the best of our knowledge, this is the first study which has addressed chemerin expression in breast cancer tissue. In this study, we found that chemerin expression was significantly higher in the cancer tissue in comparison to adjacent normal breast tissue. Moreover, chemerin expression was higher in the metastatic LNs in comparison to the tumor tissues. Its expression was strongly related to the tumor size, presence of LN or distant metastasis, and tumor grading. Similar to existing literature, chemerin levels were found to be strongly, positively correlated with weight and BMI. While chemerin levels was inversely correlated with ER and PR expression in the malignant breast tissue. Based on the ROC curve analysis, the AUC of chemerin was 0.82, with a sensitivity of 89% and specificity of 69%. The Kaplan–Meier survival curves revealed that patients with high expression of chemerin had unfavorable disease-free survival in comparison to those with low expression.

Several adipokines such as leptin, resistin, apelin, and visfatin have been implicated in cancer development through different pathophysiological mechanisms such as inflammation, insulin resistance, and sex hormones’ production. Their increased levels were reported to play a pro-carcinogenic role.4 On the contrary, other adipokines such as adiponectin were reported to have an anti-carcinogenic role.3 The recently discovered adipokine, chemerin (also known as TIG-2 or RARRES2), is a chemoattractant factor that was found to regulate adipocyte development, metabolic functions, and immunity32,33 and has been associated with obesity, metabolic syndrome, insulin resistance, inflammatory diseases, and cancer.18,20–22,25,34–38 Many reports have attempted to elucidate the pathophysiological mechanisms through which chemerin could induce its effects. Chemerin promotes tumorigenesis by triggering the production and activity of matrix metalloproteinase, which plays a crucial role in angiogenesis, while the antitumor role for high chemerin levels has been reported to be through recruitment of natural killer (NK) cells which would help the immune system to recognize and fight the cancer cells.20–23,39 Also, chemerin could induce the initiation of the innate immune response and inflammatory processes by attracting the antigen presenting cells.17,25,40Therefore, with high chemerin levels, the immune system recognizes cancer cells and fights them. The inflammatory pathogenic nature of breast cancer may represent another mechanism that may link chemerin expression with breast cancer.41,42 Breast cancer stem cells’ biology has been reported to be affected by certain immune mediators.43,44 Chemerin has also been reported to be associated with numerous pro-inflammatory cytokines related to cytotoxic cell-mediated immunity such as IL-6, IL-8, and TNF-alpha,45,46 which represent inflammatory mediators in the breast.47,48

When compared to the adjacent Barrett’s tissue, the malignant tissues of esophageal adenocarcinoma were reported to have high chemerin expression,49,50 which confirmed an association between overexpression of chemerin and chemR23 and a more invasive esophageal squamous cell carcinoma. Recently, Xu et al51 reported that chemerin expression in serum may be considered as a serum biomarker for diagnosis and prognosis in non-small-cell lung cancer patients.

Obesity, a metabolic disorder, is a well-established risk factor for the development of cancer, including breast cancer. Chemerin levels were reported to be significantly associated with obesity;19 its plasma levels are significantly heritable and may be a stimulator of angiogenesis.52 The effects of adipose-derived angiogenic factors in promotion of tumor growth have been demonstrated in experimental studies.53,54 Elevated chemerin levels secondary to obesity may further contribute to chemerin’s angiogenic properties through triggering the production and activity of the matrix metalloproteinase, formation of new capillary-like structures, and vascularization of endothelial cells.52 In agreement with Catalan et al,55 our study revealed that increased serum chemerin levels were correlated with BMI and obesity.

Although many studies have demonstrated the relationship between chemerin expression in serum and tissue and many types of tumors,6–11 for breast cancer, chemerin expression has only been studied in serum.3 It has been reported that serum chemerin levels were not associated with tumor stage in breast cancer.3 In the current study, chemerin expression in tissue was associated with unfavorable clinical and pathological variables, TNM staging, and LN and distant metastasis. Chemerin levels were higher in the metastatic LNs in comparison to malignant breast tissue, while they were negatively correlated with ER and PR expression. This was also proved by Kaplan–Meier survival curves and the ROC curve. Although further investigations are required, the results of this study may imply that increased chemerin levels might serve as a marker for diagnosis, progression, and prognosis of breast cancer patients.

This study has some limitations including, small sample size, all patients had grade II and III cancer, while no patient had grade I or IV, and lack of some investigations at our center such as Western blot analysis and verification of some upstream and downstream genes of chemerin in the tumor sections and the adjacent normal tissues. Therefore, our findings need further evaluation in prospective studies with larger sample sizes to determine a causal relationship of high chemerin expression. The expression of inflammatory and immunological markers, as the natural killer cells, in the malignant and adjacent benign tissue also, need to be clarified in further studies.

CONCLUSION

The higher chemerin expression in malignant in comparison to normal breast tissues and the increased expression in the LN metastatic tissue may introduce chemerin as an independent predictor of poor prognosis of women with breast cancer.

Disclosure

The authors report no conflicts of interest in this work.

Ghada El-Sagheer,1 Mariana Gayyed,2 Asmaa Ahmad,1 Aliaa Abd El-Fattah,3 Manar Mohamed4
1Endocrinology Unit, Department of Internal Medicine, Minia Faculty of Medicine, Minia University, Minia, Egypt; 2Department of Pathology, Minia Faculty of Medicine, Minia University, Minia, Egypt; 3Department of Internal Medicine, Minia Faculty of Medicine, Minia University, Minia, Egypt; 4Department of Internal Medicine, Deraya University, Minia, Egypt

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