Estrogen Effects on Iron Uptake by Human Mammary Cells Lines

Iron is an essential nutrient in the metabolic processes and the proliferation of cells, but iron overload has been associated with increased risk for cancer. We showed that feeding a diet high in iron doubled the incidence of estrogen-induced kidney tumors in hamsters (Wyllie and Liehr 1998). Estrogen also induced an increase in iron accumulation in hamster kidney (unpublished data). We hypothesize that estrogen-induced iron accumulation precedes estrogen-induced tumor formation. Thus, cells susceptible to development of estrogen-induced tumors will also exhibit estrogen-stimulated iron accumulation. The excess iron may cause free radical-mediated cell damage and contribute to tumor formation. We are investigating this hypothesis by studying estrogen-induced iron accumulation in two human breast cell lines: MCF7 tumor and MCF10A nontumor cells. Cells were treated with estradiol ([E.sub.2]) at 1 [micro]mol/L to 1 [micro]mol/L for 1, 3 or 7 d. For the final 24 h of each treatment period, [sup.59]Fe was present in the medium. The cells were lysed and [sup.59]Fe was counted. Values were normalized to total protein. Baseline [sup.59]Fe uptake differed between the cell lines and was passage-dependent in MCF10A cells. [E.sub.2] increased [.sup.59]Fe uptake in MCF7 breast cancer cells (but not MCF10A cells) with maximal effects at 7 d. [E.sub.2] effects were blocked by the estrogen-receptor antagonist ICI 182780. These data demonstrate that regulation of iron uptake is altered in MCF7 cancer cells and that [E.sub.2] further modifies iron uptake in these cells. Altered iron metabolism may lead to perpetual free radical-mediated mutagenesis followed by carcinogenesis, metastasis and drug resistance, indicating a role for iron in hormone-associated cancers such as breast cancer. [Supported National Institutes of Health, National Cancer Institute CA 74971.] Wyllie and Liehr. 1998 Carcinogenesis 19:1285-1290.