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.

• Authors: Shuping Zhang, Yue Chen, Wenli Guo, Lin Yuan, Daoqiang Zhang, Yong Xu, Elizabeta Nemeth, Tomas Ganz, Sijin Liu
• Journal: Cellular signalling (Cell Signal) Vol. 26 Issue 11 Pg. 2539-50 (Nov 2014) ISSN: 1873-3913 [Electronic] England
• PMID: 25093806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• BMP6 protein, human
• Bone Morphogenetic Protein 6
• Cation Transport Proteins
• Hepcidins
• IL6 protein, human
• Interleukin-6
• Neoplasm Proteins
• metal transporting protein 1

Topics

• Bone Morphogenetic Protein 6 (genetics, metabolism)
• Breast Neoplasms (genetics, metabolism, pathology)
• Cation Transport Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Female
• Hepcidins (genetics, metabolism)
• Humans
• Interleukin-6 (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Signal Transduction