title: Ferroportin and iron regulation in breast cancer progression and prognosis.
abstract: Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. Ferroportin is the only known mechanism for export of intracellular non-heme-associated iron; its stability is regulated by the hormone hepcidin. Although ferroportin profoundly affects concentrations of intracellular iron in tissues important for systemic iron absorption and trafficking, ferroportin concentrations in breast cancer and their influence on growth and prognosis have not been examined. We demonstrate here that both ferroportin and hepcidin are expressed in cultured human breast epithelial cells and that hepcidin regulates ferroportin in these cells. Further, ferroportin protein is substantially reduced in breast cancer cells compared to nonmalignant breast epithelial cells; ferroportin protein abundance correlates with metabolically available iron. Ferroportin protein is also present in normal human mammary tissue and markedly decreased in breast cancer tissue, with the highest degree of anaplasia associated with lowest ferroportin expression. Transfection of breast cancer cells with ferroportin significantly reduces their growth after orthotopic implantation in the mouse mammary fat pad. Gene expression profiles in breast cancers from >800 women reveal that decreased ferroportin gene expression is associated with a significant reduction in metastasis-free and disease-specific survival that is independent of other breast cancer risk factors. High ferroportin and low hepcidin gene expression identifies an extremely favorable cohort of breast cancer patients who have a 10-year survival of >90%. Ferroportin is a pivotal protein in breast biology and a strong and independent predictor of prognosis in breast cancer.
authors.affiliation: Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Zandra K
authors.initials: ZK
authors.lastname: Pinnix
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ralph
authors.initials: R
authors.lastname: D'Agostino
authors.forename: Tim
authors.initials: T
authors.lastname: Kute
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Heather
authors.initials: H
authors.lastname: Hatcher
authors.forename: Lia
authors.initials: L
authors.lastname: Tesfay
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Xiumin
authors.initials: X
authors.lastname: Di
authors.forename: Suzy V
authors.initials: SV
authors.lastname: Torti
authors.forename: Frank M
authors.initials: FM
authors.lastname: Torti
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000145:classification / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D027682:Cation Transport Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D011379:Prognosis; D016896:Treatment Outcome; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D000098742:Ferroportin; D007501:Iron