Expression of Chemerin Correlates With a Poor Prognosis in Female Breast Cancer Patients

Objective: Chemerin was reported to regulate adipogenesis, metabolism, and immunity. But, its relation to cancer remains controversial. In breast cancer, chemerin expression has only been studied in serum, however, its expression in tissue, to our knowledge, has not been studied. The aim of this study was to investigate chemerin expression in breast cancer tissue in comparison to the adjacent normal tissue, and to assess its relationship to disease prognosis.
Methods: We examined chemerin expression in tissue with immunohistochemistry and analyzed the association of chemerin expression with the patients’ clinical and pathological characteristics to determine its role as a predictor of the disease and its relation to disease prognosis.
Results: We detected a significantly higher expression of chemerin in the malignant vs the non-cancerous tissue specimens in 30/53, (56%) patients, (P=0.001). Moreover, its expression was significantly higher in the metastatic lymph nodes in comparison to the tumor tissues, (P=0.01). Chemerin expression was significantly correlated with weight (r=0.256, P=0.04), body mass index (r=0.233, P=0.03), tumor size (r=0.235, P=0.03), lymph node metastasis (r=0.265, P=0.045), distant metastasis (r=0.267, P=0.02), and tumor grading, (r=0.421, P=0.004), while it was inversely significantly correlated with estrogen receptor and progesterone receptor expression in malignant breast tissues (P=0.038, r=-0.437, and P=0.047, r=–0.316), respectively. The area under the receiver operating characteristic curve for chemerin as a predictor of breast cancer was 0.82, (P<0.001, sensitivity 89%, and specificity 69%). The Kaplan–Meier survival curves revealed that patients with higher chemerin expression had worse overall survival in comparison to those with a lower chemerin expression, (P=0.001).
Conclusion: Our results revealed higher chemerin expression in malignant vs adjacent normal breast tissue and lend support to a presumable role of chemerin tissue expression as an independent predictor of poor prognosis in breast cancer patients.

Keywords: chemerin expression, breast cancer, adipocyte development, obesity  

INTRODUCTION

Breast cancer represents the most common female cancer in Egypt (32%),¹ affecting one in eight women, with nearly 700,000 deaths/year worldwide.^2,3 Although the most important risk factor for breast cancer remains extended estrogen exposure by different etiologies, the exact pathophysiological mechanism has not been determined yet.

Obesity, a worldwide epidemic,⁴ has been found to be associated with different kinds of malignancies.⁵Post-menopausal obesity, an estrogen excess condition, has been reported to cause a 63% increase in breast cancer risk⁶ through many biologically active factors such as estrogen, insulin, IGF-I, leptin, and chemerin.^7–10 The periadventitial fat stores have the capacity, in various manners, to produce bioactive peptides, adipokines.^11,12 Through acting in an autocrine, paracrine, and endocrine manner, these adipokines have been shown to regulate several body functions and have been implicated in the pathophysiological mechanisms of clinical entities, including immunity, metabolism, and cancers.^4,5,13

The adipokine, chemerin, is synthesized as a 163-amino acid preproprotein (prochemerin), N-terminally cleaved with low activity.¹⁴ Following secretion, prochemerin can be C-terminally cleaved by a variety of extracellular proteases, resulting in several chemerin isoforms with varying lengths, receptor affinity, and biological activity.¹⁴ Its production from adipocytes is triggered by TNF-alpha.¹⁵Being a chemoattractant protein, chemerin acts as a ligand for the G-protein-coupled receptors; CMKLR1 (or ChemR23), GPR1, and CCRL2. Only the chemerin/CMKLR1 axis’ biological actions have been clearly described,¹⁶ and are mainly expressed in adipocytes, immune cells, and in breast tissue.¹⁷It has been reported to be involved in various inflammatory diseases, as well as different malignancies.¹⁸ Chemerin has been identified to regulate adipogenesis and is associated with metabolic syndrome, polycystic ovary syndrome, and obesity.^3,14,16,19

Chemerin’s association with cancer is not clearly understood.³ The conflicting reports about the link between chemerin and cancer have caused this relation to be controversial, with reported tumorigenic and antitumor effects. While chemerin/CMKLR1 showed a tumorigenesis effect in squamous cell carcinoma of the oral tongue, glioblastoma, squamous esophageal cancer, gastric cancer^20–23 and was shown to be extensively produced by neuroblastoma cells (tumor cell growth could be impaired by inhibition of the chemerin/CMKLR1 axis in vitro and in vivo),²⁴ down-regulation or an antitumorigenic effect has been suggested in hepatocellular carcinoma, non-small-cell lung cancer, and melanoma.^25–27The expression of chemerin in inflamed tissues, its pro- and anti-inflammatory properties, and its chemotactic recruitment of macrophages and other cells expressing CMKLR1 receptor, elucidate its role in inflammatory states.^16,28 High chemerin levels may have an initiating role in carcinogenesis by promoting angiogenesis through inducing matrix metalloproteinase secretion and activity.²⁹ Few studies have investigated chemerin expression in serum and tissue in gastric, colon, lung and esophageal cancers, and melanoma. In breast cancer, while chemerin expression has been extensively studied in serum, it has not been studied in malignant breast tissues.³ This study was designed to determine chemerin expression in the malignant tissue of women suffering from breast cancer in comparison to the adjacent normal tissue, and to assess its relationship with disease prognosis.