Title: Effects of iron deficiency and iron overload on angiogenesis and oxidative stress-a potential dual role for iron in breast cancer.
Authors: Jian, Jinlong; Yang, Qing; Dai, Jisen; Eckard, Jonathan; Axelrod, Deborah; Axelrod, Debrah; Smith, Julia; Huang, Xi
Published In Free Radic Biol Med, (2011 Apr 1)
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-1ýý. 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.
PubMed ID: 21193031
MeSH Terms: Anemia, Iron-Deficiency/complications; Anemia, Iron-Deficiency/metabolism; Animals; Breast Neoplasms/etiology; Breast Neoplasms/metabolism; Breast Neoplasms/physiopathology; Cell Line, Tumor; Estrogens/metabolism; Estrogens/pharmacology*; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Iron Overload/complications; Iron Overload/metabolism*; Iron, Dietary/metabolism*; Iron/metabolism*; Iron/pharmacology; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases/genetics; Mitogen-Activated Protein Kinases/metabolism*; Neovascularization, Pathologic/complications; Neovascularization, Pathologic/metabolism; Oxidative Stress/drug effects; Postmenopause/metabolism; Premenopause/metabolism; Transcriptional Activation/drug effects; Up-Regulation; Vascular Endothelial Growth Factor A/genetics; Vascular Endothelial Growth Factor A/metabolism*