title: Effects of iron deficiency and iron overload on angiogenesis and oxidative stress-a potential dual role for iron in breast cancer.
abstract: Estrogen alone cannot explain the differences in breast cancer (BC) recurrence and incidence rates in pre- and postmenopausal women. In this study, we have tested a hypothesis that, in addition to estrogen, both iron deficiency due to menstruation and iron accumulation as a result of menstrual stop play important roles in menopause-related BC outcomes. We first tested this hypothesis in cell culture models mimicking the high-estrogen and low-iron premenopausal condition or the low-estrogen and high-iron postmenopausal condition. Subsequently, we examined this hypothesis in mice that were fed iron-deficient and iron-overloaded diets. We show that estrogen only slightly up-regulates vascular endothelial growth factor (VEGF), an angiogenic factor known to be important in BC recurrence. It is, rather, iron deficiency that significantly promotes VEGF by stabilizing hypoxia-inducible factor-1α. Conversely, high iron levels increase oxidative stress and sustain mitogen-activated protein kinase activation, which are mechanisms of known significance in BC development. Taken together, our results suggest, for the first time, that an iron-deficiency-mediated proangiogenic environment could contribute to the high recurrence of BC in young patients, and iron-accumulation-associated pro-oxidant conditions could lead to the high incidence of BC in older women.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Jian
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Jisen
authors.initials: J
authors.lastname: Dai
authors.forename: Jonathan
authors.initials: J
authors.lastname: Eckard
authors.forename: Deborah
authors.initials: D
authors.lastname: Axelrod
authors.forename: Debrah
authors.initials: D
authors.lastname: Axelrod
authors.forename: Julia
authors.initials: J
authors.lastname: Smith
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000150:complications / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D019190:Iron Overload / Q000150:complications / Q000378:metabolism*; D019266:Iron, Dietary / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000150:complications / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017698:Postmenopause / Q000378:metabolism; D017697:Premenopause / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019266:Iron, Dietary; D042461:Vascular Endothelial Growth Factor A; D007501:Iron; D020928:Mitogen-Activated Protein Kinases