<p>Inflammation Mediated Hepcidin-Ferroportin Pathway and Its Therapeutic Window in Breast Cancer</p>

Abstract

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.

An Integrated Systematic Analysis and the Clinical Significance of Hepcidin in Common Malignancies of the Male Genitourinary System

“…As revealed by the data extracted from TCGA, the correlation between hepcidin and immune cell content had a significant impact on the OS in patients with KIRC. Several studies have shown that hepcidin-associated immune cell infiltration is involved in the development of cancers ( Shibabaw et al, 2020 ; Fan et al, 2021 ), but renal cancer was never mentioned. In this study, the infiltration of most immune cells was linked with elevated hepcidin levels, including those of macrophages, natural killer T cells, B cells, CD4 + memory CD8 + T cells, mesenchymal stem cells, type 1 T-helper cells, type 2 T-helper cells, and regulatory T cells.…”

“…Therefore, regulating iron metabolism can be used as an antitumor strategy ( Hsu et al, 2020 ; Lelièvre et al, 2020 ). Hepcidin has also been previously reported to play an important role in digestive system tumors, including colorectal cancer ( Sornjai et al, 2020 ; Colorectal Cancer Cells Ectopically Express Hepcidin to Sequester Iron, 2021 ; Schwartz et al, 2021 ), gastric cancer ( Jakszyn et al, 2017 ), pancreatic cancer ( Toshiyama et al, 2018 ), and hepatocellular carcinoma ( Abd Elmonem et al, 2009 ; Udali et al, 2018 ; Wang et al, 2019 ), as well as in thoracic cancers such as breast cancer ( Blanchette-Farra et al, 2018 ; El-Mahdy et al, 2020 ; Jerzak et al, 2020 ; Shibabaw et al, 2020 ; Blindar et al, 2021 ) and lung cancer ( Chen et al, 2014 ; Fan et al, 2021 ). Collectively, hepcidin appears to play an important role in cancer.…”

Iron Therapeutics in Women’s Health: Past, Present, and Future

“…Current clinical trials of hepcidin antagonism are primarily centered around malignancy induced anemia of chronic disease and other hematological disorders, although quinoxaline, a small molecule that prevents degradation of the ferroportin receptor was shown to have in vitro activity against the MCF7 breast cancer cell line [153,158]. Previous work has shown that low hepcidin levels in breast cancer cell lines was of particularly favorable prognosis, which may be related to the concentration of intracellular iron and the creation of ROS, driving cancer progression [65,66]. Furthermore, disruption of intracellular iron signaling also has been shown a useful adjuvant agent to traditional chemotherapy for ovarian and breast cancer [159].…”

Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial–Mesenchymal Transition and Correlates with Progression of the Disease

“…Moreover, hepcidin promoter DNA is hyper-methylated in HCC, resulting in its transcriptional repression [ 18 ]. On the other hand, reduced hepatic hepcidin expression was found to be protective against the progression of lung and breast cancer [ 19 ]. Moreover, in patients with breast cancer, hepcidin expression is significantly upregulated in tissues and serum and there is evidence supporting the role of hepcidin in the development of the malignant phenotype and resistance to doxorubicin [ 20 , 21 , 22 ].…”