Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Abstract

Iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including cancers. Burgeoning evidence indicates that the central signaling of iron homeostasis, the hepcidin-ferroportin axis, is misregulated in cancers. Nonetheless, the mechanisms of misregulated expression of iron-related genes along this signaling in cancers remain largely unknown. In the current study, we found increased levels of serum hepcidin in breast cancer patients. Reduction of hepatic hepcidin through administration of heparin restrained tumorigenic properties of breast tumor cells. Mechanistic investigation revealed that increased iron, bone morphogenetic protein-6 (BMP6) and interleukin-6 (IL-6) jointly promoted the synthesis of hepatic hepcidin. Tumor hepcidin expression was marginally increased in breast tumors relative to adjacent tissues. In contrast, tumor ferroportin concentration was greatly reduced in breast tumors, especially in malignant tumors, compared to adjacent tissues. Elevation of ferroportin concentration inhibited cell proliferation in vitro and in vivo by knocking down tumor hepcidin expression. Additionally, increased IL-6 was demonstrated to jointly enhance the tumorigenic effects of iron through enforcing cell growth. Our combined data overall deciphered the machinery that altered the hepcidin-ferroportin signaling in breast cancers. Thus, targeting the hepcidin-ferroportin signaling would represent a promising therapeutics to restrain breast cancer growth.

Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element

“…FPN plays a crucial role in maintaining the concerted iron homeostasis through controlling iron egress, and dysregulation of FPN would give rise to disordered iron metabolism, [10] likely resulting in FPN diseases, such as hereditary hemochromatosis and β-thalassemia [5]. Additionally, we also recently found reduced level of FPN in breast cancers, associated with poor prognosis in breast cancer patients [11,30]. To keep the balance of systemic iron metabolism, FPN is predominantly regulated by hepcidin through binding and inducing ubiquitin-dependent proteasomal degradation of FPN protein [6].…”

“…This study provides additional explanation for body iron changes in women upon estrogen alterations, such as a dramatic decline in the estrogen level in postmenopausal women. Since increased serum iron and tissue iron retention were observed in postmenopausal women, [30,66] excess iron would likely incur in detrimental effects on health. Therefore, in addition to its pronounced role in ameliorating menopausal symptoms, administration of a proper dose of estrogen (namely estrogen replacement therapy) might help to orchestrate systemic iron homeostasis.…”

“…Cells were washed with ice cold PBS and then lysed in RIPA lysis buffer (Solarbio, China) supplemented with protease inhibitor cocktail (Roche), as previously described [30]. An equal amount of each lysate (80-100 μg/sample) was subjected to 10% sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) and transferred to nitrocellulose membranes afterwards.…”

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

“…Hepcidin induction in this cancer requires BMP2, another BMP/SMAD pathway ligand, and the inflammatory cytokine . Furthermore, recent work demonstrated that hepcidin is elevated in breast cancer patients and that diminished tumor expression of ferroportin promotes breast cancer growth (86,87). Finally, patients with the most advanced cancers have the lowest RBC hemoglobin concentration, and hemoglobin measurements are conversely correlated with inflammatory markers and hepcidin (88).…”

EPO-dependent induction of erythroferrone drives hepcidin suppression and systematic iron absorption under phenylhydrazine-induced hemolytic anemia

“…The molecular basis of hepcidin function is to induce iron exporter ferroportin internalization and degradation within lysosomes through an ubiquitin-dependent manner, by which iron efflux out of macrophages and intestinal absorption would be inhibited [9,10]. Hepcidin expression is promoted by excess iron and inflammation, and is reversely suppressed by erythropoiesis and hypoxia [6,[9][10][11][12]. These different ways in the regulation of hepcidin concertedly limit intestinal iron absorption during iron overload, and increase iron availability during erythropoiesis, e.g.…”