title: IRP2 regulates breast tumor growth.
abstract: Experimental and epidemiologic evidence suggests that dysregulation of proteins involved in iron metabolism plays a critical role in cancer. The mechanisms by which cancer cells alter homeostatic iron regulation are just beginning to be understood. Here, we demonstrate that iron regulatory protein 2 (IRP2) plays a key role in iron accumulation in breast cancer. Although both IRP1 and IRP2 are overexpressed in breast cancer, the overexpression of IRP2, but not IRP1, is associated with decreased ferritin H and increased transferrin receptor 1 (TfR1). Knockdown of IRP2 in triple-negative MDA-MB-231 human breast cancer cells increases ferritin H expression and decreases TfR1 expression, resulting in a decrease in the labile iron pool. Further, IRP2 knockdown reduces growth of MDA-MB-231 cells in the mouse mammary fat pad. Gene expression microarray profiles of patients with breast cancer demonstrate that increased IRP2 expression is associated with high-grade cancer. Increased IRP2 expression is observed in luminal A, luminal B, and basal breast cancer subtypes, but not in breast tumors of the ERBB2 molecular subtype. These results suggest that dysregulation of IRP2 is an early nodal point underlying altered iron metabolism in breast cancer and may contribute to poor outcome of some patients with breast cancer.
authors.affiliation: Authors' Affiliations: Departments of Pathology, Cancer Biology, and Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina; Departments of Molecular, Microbial and Structural Biology and Internal Medicine, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Deng
authors.forename: Heather
authors.initials: H
authors.lastname: Hatcher
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.forename: Xiumin
authors.initials: X
authors.lastname: Di
authors.forename: Lia
authors.initials: L
authors.lastname: Tesfay
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Ralph B
authors.initials: RB
authors.lastname: D'Agostino
authors.forename: Frank M
authors.initials: FM
authors.lastname: Torti
authors.forename: Suzy V
authors.initials: SV
authors.lastname: Torti
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001052:Apoferritins / Q000378:metabolism; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007501:Iron / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011990:Receptors, Transferrin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D001052:Apoferritins; D007501:Iron; C546174:IREB2 protein, human; D035942:Iron Regulatory Protein 2