Deferoxamine-induced increase in the intracellular iron levels in highly aggressive breast cancer cells leads to increased cell migration by enhancing TNF-α-dependent NF-κB signaling and TGF-β signaling

Recent studies have suggested that excess iron accumulation may be a risk factor for breast cancer. However the role of iron in breast cancer metastasis has remained unclear. The major goal of our study is to investigate the roles of iron in breast cancer metastasis. We modulated the intracellular iron levels of human breast cancer cells, including the aggressive MDA-MB-231 cells and non-aggressive MCF-7 cells, by using Deferoxamine (DFO) - a most widely used iron chelator. We found that DFO treatment could deplete intracellular iron in MCF-7 cells. In contrast, DFO treatment led to a significant increase in the intracellular iron level in MDA-MB-231 cells. The MDA-MB-231 cells with the increased intracellular iron level exhibited increases in both mesenchymal markers and cell migration. Furthermore, the DFO-treated MDA-MB-231 cells showed increases in both tumor necrosis factor alpha (TNF-alpha)-induced nuclear factor kappa B (NF-kappa B) signaling and transforming growth factor-beta (TGF-beta) signaling, which could contribute to the enhanced cell migration. Collectively, our study has provided the first evidence suggesting that increased intracellular iron levels could lead to enhanced migration of aggressive breast cancer cells by increasing TNF-alpha-dependent NF-kappa B signaling and TGF-beta signaling. Our study has also suggested that caution should be taken when DFO is applied for treating breast cancer cells, since DFO could produce differential effects on the intracellular iron levels for aggressive breast cancer cells and non-aggressive breast cancer cells. (C) 2016 Elsevier Inc. All rights reserved.