Effects of iron deficiency and iron overload on angiogenesis and oxidative stress-a potential dual role for iron in breast cancer.

Estrogen alone cannot explain the differences in breast cancer (BC) recurrence and incidence rates in pre- and postmenopausal women. In the present 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 and the low estrogen and high iron postmenopausal condition, respectively. Subsequently, we examined this hypothesis in mice that were fed iron deficient and iron overload diets. We have shown 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 (HIF-1α). Conversely, high iron levels increase oxidative stress and sustain mitogen-activated protein kinase (MAPK) activation, which are mechanisms of known significance in BC development. Taken together, our results suggest, for the first time, that an iron deficiency-mediated pro-angiogenic 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.