Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis.

Human breast cancer MDA-MB-231 cells were transfected with transferrin receptor-1 (TfR1) shRNA to constitutively impair iron uptake. Cellular iron status was determined by a set of iron proteins and angiogenesis was evaluated by levels of VEGF in cells as well as by a mouse xenograft model. Significant decreases in ferritin with concomitant increases in VEGF were observed in TfR1 knockdown MDA-MB-231 cells when compared to the parental cells. TfR1 shRNA transfectants also evoked a stronger angiogenic response after the cells were injected subcutaneously into nude mice. The molecular mechanism appears that cellular iron deficiency elevates VEGF formation by stabilizing HIF-1α. This mechanism is also true in human breast cancer MCF-7 and liver cancer HepG2 cells.Cellular iron deficiency increased HIF-1α, VEGF, and angiogenesis, suggesting that systemic iron deficiency might play an important part in the tumor angiogenesis and recurrence in this young age group of breast cancer patients.Young women (< 45 years old) diagnosed with breast cancer are well known to have a higher risk of dying from the disease than older patients because of greater early recurrence rates, increased aggressiveness, and mostly estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2) negative or triple negative breast tumors [1,2]. The specific risk factors contributing to this poorer outcome in young patients have not been identified. Although a decline in total breast cancer cases was recently reported, a plot of age-specific breast cancer rates shows a decrease only among women >45 years old [3]. This dilemma calls for new research on identification of additional risk factors in this young group of patients.Using data initially collected from the New York University Women's Health Study, we observed that serum iron and ferritin levels are significantly lower in pre- than in postmenopausal women [4]. A typical characteristic of young pre-menopaus