Breast Cancer: Targets and Therapy (Oct 2020)
Inflammation Mediated Hepcidin-Ferroportin Pathway and Its Therapeutic Window in Breast Cancer
Abstract
Tewodros Shibabaw,1 Banchamlak Teferi,2 Meseret Derbew Molla,1 Birhanu Ayelign3 1Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 2Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 3Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, EthiopiaCorrespondence: Tewodros Shibabaw Tel +251 910162171Email [email protected]: Experimental and clinical data strongly support that iron is an essential element which plays a big role in cancer biology. Thus, hepcidin (Hp) and ferroportin (Fpn) are molecules that regulate and maintain the metabolism of iron. A peptide hormone hepcidin limits recycled and stored iron fluxes in macrophage and hepatic hepatocyte, respectively, to the blood stream by promoting degradation of the only iron exporter, Fpn, in the target cells. Moreover, the inflammatory microenvironment of breast cancer and altered hepcidin/ferroportin pathway is intimately linked. Breast cancer exhibits an iron seeking phenotype that is accomplished by tumor-associated macrophage (TAM). Because macrophages contribute to breast cancer growth and progression, this review will discuss TAM with an emphasis on describing how TAM (M2Ф phenotypic) interacts with their surrounding microenvironment and results in dysregulated Hp/Fpn and pathologic accumulation of iron as a hallmark of its malignant condition. Moreover, the underlying stroma or tumor microenvironment releases significant inflammatory cytokines like IL-6 and bone morphogenetic proteins like BMP-2 and 6 leading in aberrant Hp/Fpn pathways in breast cancer. Inflammation is primarily associated with the high intracellular iron levels, deregulated hepcidin/ferroportin pathway, and its upstream signaling in breast cancer. Subsequently, scholars have been reported that reducing iron level and manipulating the signaling molecules involved in iron metabolism can be used as a promising strategy of tumor chemotherapy. Here, we review the key molecular aspects of iron metabolism and its regulatory mechanisms of the hepcidin/ferroportin pathways and its current therapeutic strategies in breast cancer.Keywords: breast cancer, hepcidin, ferroportin, inflammation, upstream signaling, bone morphogenetic proteins, tumor-associated macrophage
