Changes in estrogen levels during menopausal transition have been considered a unique feature in women and the effects of estrogen on BC are well documented (Clemons et al, 2001). Separate studies on estrogen and iron as a function of age and menopausal status have concluded to younger pre-menopausal women have high systemic estrogen but low iron levels (Huang, 2008). Older post-menopausal women have low systemic estrogen but high iron levels (Subramanian et al, 2008).
This observation led the development of simple tissue culture models that simultaneously mimic levels of iron and estrogen in pre- and postmenopausal women and the detection of the inhibitory effects of ferritin on Vascular Endothelial Growth Factor (VEGF) and its enhancing and sustaining effects on oxidative stress and Mitogen-Activated Protein Kinases (MAPK) activation. VEGF is a signal protein produced by cells and is part of the system that restores the oxygen supplies to tissues when blood circulation is inadequate while MAPK are serine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities. This initial finding led further investigation with human skin biopsy samples of pre- and postmenopausal women. Data obtained from the present study have shown a possible pro-angiogenic environment in young women and a pro-oxidant environment in older women. This is consistent with previous reports showing that levels of VEGF in normal breast tissue as well as in breast tumors were significantly higher in pre- than in post-menopausal subjects (Fuckar et al, 2006). This finding is clinically relevant because it supports two notions: age is associated with decreased vascular repair and neovascularization and impaired Hypoxia-Inducible Factor (HIF) pathways, transcription factors that respond to changes in available oxygen in the cellular environments (Hoenig et al, 2008); systemic iron deficiency or lack of ferritin is a driving force for increased VEGF levels in young women (Kell et al, 2009).
Iron deficiency and iron deficiency anemia (IDA) affect 20% of non-pregnant women aged 16 to 49 in industrialized countries and half of all women in developing countries (Zimmermann et al, 2007). Systemic iron deficiency in young women may provide a pro-angiogenic environment that favors the HIF-1α induction and stabilization leading to increased VEGF formation and angiogenesis. Two distinguished mechanisms may exist in HIF regulation. First, at the systemic level, iron deficiency and IDA induce HIF-1α because fewer red blood cells transport oxygen in the body of young women, resulting in a hypoxic condition in the breasts (Vaupel et al, 2005). An association between low iron levels measured as hemoglobin and increased serum VEGF was reported in cancer patients (Dunst et al, 1999). A correlation was also established between anemia and intratumoral hypoxia (Vaupel et al, 2005). Second, at the cellular and tissue levels, iron deficiency and IDA stabilize HIF-1α by lowering HIF-degrading prolyl hydroxylases (Kaelin et al, 2008) because iron is a co-factor of the enzymes (Smith et al, 2008). Indeed, lack of iron in cells grown under premenopausal leads to a stronger HIF-1α band than the same cells grown under postmenopausal condition with abundant iron. Therefore, iron deficiency in young women may, by increasing HIF-1α and VEGF levels, enhance angiogenesis and metastasis and, consequently, higher tumor grades and greater recurrence rates in young BC patients (Huang, 2008).
The majority of serum E2 in premenopausal women is derived from ovarian secretion and subsequently distributed through the bloodstream in an endocrine fashion. Although breast tissue estrogen levels are comparable between pre- and postmenopausal women, accumulated breast exposure to estrogen cannot fully explain a 5-fold increase in BC incidence in post-menopausal women (Huang, 2008). A large clinical trial has shown that iron reduction through phlebotomy lowers cancer risk and mortality (Zacharski et al, 2008). Both estrogen and iron are considered cancer promoters and have been shown to synergistically enhance cell proliferation in ER+ cells (Dai et al, 2007). Elevated dietary iron intake also significantly increases estrogen-induced kidney tumors in Syrian hamsters (Wyllie et al, 1998) and high levels of ferritin are detected in BC tissue samples (Higgy et al, 1997). Thus, increased iron levels after menopause, along with high estrogen levels at the local breast tissues, may play important roles in the increased BC incidence in post-menopausal women.
Most research involving iron in cancer has been focused on iron overload causing oxidant-mediated cancer promotion (Grant, 2008). Iron deficiency in young women may contribute to the poor prognosis observed in this young age group of BC patients. Conversely, increased iron levels in post-menopausal women due to menstrual cessation may lead to higher BC incidence rates via oxidative stress pathway. For the first time, data suggest that iron could be a risk factor affecting BC outcomes before and after menopause and, thus, iron could be equally important as estrogen. Understanding the role of iron imbalance in breast cancer can help doctors find better therapeutic treatments and potentially benefit patients by decreasing recurrence and incidence.
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