Breast cancer is the most frequent cancer among women accounting for 24.2% of all female cancers and it is the most common cause of death from cancer in women as its mortality ratio is about 15% [16]. Distant breast cancer causes the majority of these deaths because cancer in these cases has reached organs outside of the breasts like bones, lungs, liver, or brain. Although breast cancer treatment methods are increased and improved, the 5-year survival rate of distant breast cancer patients remains relatively low as the distant metastases may cause a secondary cancer in other organ. According to the American Cancer Society, the 5-year relative survival rate for distant breast cancer is 27% ,whereas it is 86% for regional breast cancer [17].
The early detection of breast cancer and its metastasis opens the door to more treatment options, higher treatment efficacy and higher survival rates. It is also important for improving patient prognosis and outcomes as it helps saving their lives. At present, the detection of distant metastases has limitations and requires long time and high cost. The development of additional molecular biomarkers is strongly required and a simple non-invasive test on an easy obtainable sample for the early detection of patients with breast cancer metastasis is therefore sought after.
S100A14 is one of the newest members of the S100 calcium binding protein family that has gained increased interest in cancer researches as it plays various roles that are related to carcinogenesis such as cell proliferation, cell invasion and motility, cell differentiation, and regulation of transcription factors like tumor protein p53 [1]. Many studies revealed that altering in S100A14 expression is associated with cancer progression and prognosis [10, 18, 19]. Previous studies have also clearly revealed the presence of S100A14 in serum as it is secreted by cancer cells and exerts extracellular functions [20, 21]. Therefore, we aimed in this study to determine the levels of S100A14 protein in serum samples of breast cancer patients and healthy individuals.
Studies suggested many theories about the working mechanism of S100A14. A study on esophageal squamous cell carcinoma reported that the extracellular S100A14 protein binds to RAGE receptor (receptor for advanced glycation end products) leading to modulating of RAGE signaling, as the engagement of RAGE with S100A14 triggers activation of mitogen activated protein (MAP) kinase and nuclear factor κB (NF-κB) signaling pathways [2]. While the over signaling of MAP kinase pathway causes altering in cell proliferation and survival to an abnormal manner, NF-κB-signaling pathway establishes a microenvironment which is crucial for either cancer initiation or development, or both by increasing cellular metabolic activity and cell division [22].
Another study identified CCL2 (chemokine (C-C motif) ligand 2) as a downstream target of S100A14. CCL2 is a chemokine secreted from cancer cells, it initiates chemokine cascade that results in TAM (tumor-associated macrophage) recruitment [10]. These TAMs contribute to cancer progression by secreting extracellular vesicles contain signal molecules like PDGF (platelet-derived growth factor) that promote tumor growth, VEGF (vascular endothelial growth factor) that induce angiogenesis, and MMPs (matrix metalloproteinases) which are important for tumor migration, invasion, and metastasis [23].
These findings may explain the elevation in serum levels of S100A14 protein in breast cancer patients compared with healthy individuals in our study. Moreover, our results agree with a recent study suggested that the S100A14 serum level may be used as a potential biomarker for detecting breast cancer [10].
Our study revealed that S100A14 serum levels in distant breast cancer patients were significantly higher compared with other breast cancer patients. This result suggests that S100A14 may be implicated in cancer metastasis process.
This result supports another study that demonstrated that S100A14 can promote breast cancer cell invasion by regulating MMP2 (matrix metalloproteinase2) transcription in a p53-dependent way, as MMP2 is a protease responsible for degrading the multiple components of the extracellular matrix of cancer cell which is an important initial step in cancer cells invasion and metastasis process [11].
Furthermore, our study suggests that S100A14 serum level may be used as a biomarker that enhances our accuracy in identifying patients with distant metastasis, and hence provide useful information for medical management.
Strong correlation was found in our study between S100A14 serum level and the tumor grade. The higher the level of serum S100A14, the poorer the differentiation of the tumor, which indicates that this protein might inhibit cell differentiation. This result agrees with a previous report that demonstrated that high S100A14 expression was correlated with poor tumor differentiation. Moreover, that study suggested that S100A14 overexpression might be a significantly prognostic indicator of patients with breast cancer [13].
This study has many limitations which were because of limited self-funding; the first limitation is the number of participants which we could not make bigger. The second limitation is the lack of an in vitro or histological supporting study.
