title: Disordered signaling governing ferroportin transcription favors breast cancer growth.
abstract: Iron is a necessary chemical element needed by all organisms. Iron metabolism is finely tuned in mammals, and the hepcidin-ferroportin (FPN) axis is the central signaling in governing systemic iron homeostasis. Deregulation of this signaling would lead to iron disorders and likely other diseases including cancers. Reduced FPN was previously found to correlate with poor prognosis in breast cancer patients. Nonetheless, the biological effects of abnormal FPN expression in tumor cells remain largely unexplored, and the mechanisms underlying misregulated expression of FPN in cancers keep elusive. In the current study, we scrutinized the effects of abnormal FPN on tumor growth and the molecular mechanisms of diminished tumor FPN. Downregulation of FPN significantly promoted breast cancer growth, whereas FPN upregulation impeded tumor growth. We demonstrated that the transcription factors Nrf2 (nuclear factor erythroid 2-like 2) and MZF-1 (myeloid zinc finger-1) synergistically transactivated FPN expression in breast cancer cells. Moreover, CpG island methylation at the FPN promoter was the reason of attenuated FPN expression. Downregulation of Nrf2 and MZF-1 and hypermethylation of the FPN promoter were concurrently associated with decreased FPN concentration in breast tumors. Taken together, our study highlighted the contribution of disordered iron metabolism to breast cancer growth, and also signified an oncogenic effect of misregulated ferroportin in breast cancers. This work represents a promising starting point to the possibility of restraining breast cancer through targeting FPN or its upstream regulatory factors.
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Shuping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Weifang Medical College, Wendeng Central Hospital, Weihai 264400, China.
authors.forename: Daoqiang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Weifang Medical College, Wendeng Central Hospital, Weihai 264400, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China. Electronic address: xuyong8816@sina.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Sijin
authors.initials: S
authors.lastname: Liu
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000098742:Ferroportin
keywords: FPN; Iron; MZF-1; Methylation; Nrf2; Transcriptional regulation