Abstract
BackgroundThe failure of treatment for breast cancer usually results from distant metastasis in which the epithelial-mesenchymal transition (EMT) plays a critical role. Hyperinsulinemia, the hallmark of Type 2 diabetes mellitus (T2DM), has been regarded as a key risk factor for the progression of breast cancer. Nuclear receptor subfamily 2, group F, member 2 (NR2F2) has been implicated in the development of breast cancer, however its contribution to insulin-induced EMT in breast cancer remains unclear.MethodsOverexpression and knockdown of NR2F2 were used in two breast cancer cell lines, MCF-7 and MDA-MB-231 to investigate potential mechanisms by which NR2F2 leads to insulin-mediated EMT. To elucidate the effects of insulin and signaling events following NR2F2 overexpression and knockdown, Cells’ invasion and migration capacity and changes of NR2F2, E-cadherin, N-cadherin and vimentin were investigated by real-time RT-PCR and western blot.ResultsInsulin stimulation of these cells increased NR2F2 expression levels and promoted cell invasion and migration accompanied by alterations in EMT-related molecular markers. Overexpression of NR2F2 and NR2F2 knockdown demonstrated that NR2F2 expression was positively correlated with cell invasion, migration and the expression of N-cadherin and vimentin. In contrast, NR2F2 had an inverse correlation with E-cadherin expression. In MDA-MB-231, both insulin-induced cell invasion and migration and EMT-related marker alteration were abolished by NR2F2 knockdown.ConclusionsThese results suggest that NR2F2 plays a critical role in insulin-mediated breast cancer cell invasion, migration through its effect on EMT.
Highlights
The failure of treatment for breast cancer usually results from distant metastasis in which the epithelial-mesenchymal transition (EMT) plays a critical role
After starving for 12 h, monolayer cells were treated with or without insulin for 48 h, and the filter was washed, stained and photographed under a microscope. *P < 0.05, ** P < 0.01 vs. control study illustrated that hyperinsulinemia promotes proliferation, migration and invasion of the human breast cancer cell line MDA-MB-231 by upregulation of urokinase plasminogen activator and its activation depends on production of reactive oxygen species (ROS) [9, 10]
Insulin promotes the migration and invasion of breast cancer cells The effect of insulin on cell migration and invasion was evaluated in a mesenchymal type (MDA-MB-231) and epithelial type (MCF-7) cancer cells
Summary
The failure of treatment for breast cancer usually results from distant metastasis in which the epithelial-mesenchymal transition (EMT) plays a critical role. Hyperinsulinemia, the hallmark of Type 2 diabetes mellitus (T2DM), has been regarded as a key risk factor for the progression of breast cancer. Accumulating evidence indicates that type 2 diabetes mellitus (T2DM) increases the risk of developing breast cancer [1, 2]. A and b MDA-MB-231 cells and c and d MCF-7 cells were scratched by a micropipette tip and incubated with or without insulin for 24 h (both n = 4). Insulin promotes the growth of breast cancer cells in nude mice, and increases the proliferation and migration of MCF-7 human breast cancer cell line by upregulating insulin receptor substrate 1 and activating the Ras/Raf/ ERK pathway [11, 12]
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