Mediation considerations: serum potassium and the racial disparity in diabetes risk.

lack of the discussion of 2 important issues that may contribute to breast cancer in this older population: 1) the limited role dietary iron plays in determination of body iron stores and 2) the known remarkable increase in tissue iron stores that occurs after menopause (2). Because there are no known excretory pathways for iron, systemic iron homeostasis is strictly controlled by regulation of gut iron uptake though the liver-derived hormone hepcidin and the enterocyte iron exporter ferroportin for both inorganic dietary iron and heme iron (3). This highly sensitive mechanism regulates iron gut absorption to compensate for iron loss, which occurs through sloughed mucosal cells and skin desquamation (1–2 mg/d). This amount of gut iron absorption represents ,0.05% of the total body iron stores (4–5 g) and is largely independent of dietary iron content (4). Null results observed in many epidemiologic studies attempting to associate dietary iron with the breast cancer risk (1) and, more broadly, in all dietary iron and cancer risk studies (5) could be partly attributable to this regulatory system. Among all known risk factors of breast cancer, estrogen status is one of the most important (6). Yet, breast cancer incidence significantly increases after menopause during the period when overall estrogen amount is decreased by 90%. As a result of cessation of menstrual blood loss, body iron stores are increased 2–3-fold during menopausal transition (2). This significant iron increase, along with estrogen locally produced in the breast tissue by aromatase cytochrome P450, the product of CYP19A1, could increase risk of breast cancer development in older women (7). Putting estrogen and iron in this context, it would be difficult to detect the significance of iron by comparing the iron overload in patients such as hemochromatosis mutation carriers with normal controls because of the low amounts of estrogen due to hypogonadism in the iron overload patients (8, 9). To further delineate the potential role of iron in the pathophysiology of breast cancer in postmenopausal women, additional studies with direct measurement of serum ferritin or, better yet, breast tissue concentrations of ferritin and ferroportin are needed. To this extent, stronger association can be found (10), and the role of iron in breast cancer of postmenopausal women may be unarguably shown.