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Cell Signal. 2014 Nov;26(11):2539-50. doi: 10.1016/j.cellsig.2014.07.029. Epub 2014 Aug 3.

Disordered hepcidin-ferroportin signaling promotes breast cancer growth.

Author information

1
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China.
3
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
4
Weifang Medical College, Wendeng Central Hospital, Weihai 264400, China.
5
Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China.
6
Department of Medicine, David Geffen School of Medicine, University of California - Los Angeles, Los Angeles, CA 90095, USA.
7
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address: sjliu@rcees.ac.cn.

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.

KEYWORDS:

Breast cancer; Ferroportin; Hepcidin; Iron

PMID:
25093806
DOI:
10.1016/j.cellsig.2014.07.029
[Indexed for MEDLINE]

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