Changes in iron status may affect breast cancer outcomes in pre- and post-menopausal women

3698 Estrogen and family history are two of the most important risk factors in breast cancer. Yet, estrogen and family history cannot explain the differences in breast cancer recurrence and incidence rates between pre- and post-menopausal women. In the present study, we have tested a hypothesis that in pre-menopausal women, an iron deficiency due to menstruation stabilizes hypoxia inducible factor-1α, a transcriptional signaling factor which increases vascular endothelial growth factor (VEGF) formation. This mechanism makes the pre-menopausal patients more susceptible to angiogenesis and, consequently, leads to higher recurrence rates. Conversely, increased iron levels in post-menopausal women due to menstrual period cessation contribute to higher breast cancer incidence rates via oxidative stress pathway. Because there is a lack of animal models simultaneously mimicking menopausal transition of both iron and estrogen levels, we first tested our hypothesis in a tissue culture model of high estrogen and low iron (17β-estradiol and apo-transferrin) or low estrogen and high iron (holo-transferrin and ferritin), simulating pre- and post-menopausal conditions. We found that breast cancer MCF-7 cells and primary human normal epidermal keratinocytes (NHEK) cells grown under pre-menopausal conditions lead to significantly higher levels of VEGF than those from the same cells grown under post-menopausal conditions. By testing each component separately, we further found that estrogen slightly up-regulated VEGF and it was ferritin that significantly suppressed VEGF. On the contrary, more alterations in oxidative stress were observed in cells grown under post- as compared to the same cells grown under pre-menopausal conditions. Using Affymetrix genechip® technology, we identified approximately 140 genes that were altered in primary NHEK cells by post-menopausal conditions but no gene modifications in cells grown under pre-menopausal conditions as compared to cells without treatment. We then extended our studies using human biopsies from pre- and post-menopausal skin. It was found that levels of ferritin inversely correlated with levels of VEGF. Our study indicates that iron, a growth nutrient as important as estrogen in female metabolism and development, and its change during menopausal transition, may hold key information and explanations to breast cancer outcomes. This work is partly supported by R21 CA132684.