The Four-and-a-half LIM protein 1 (FHL-1) is a member of LIM-only protein family. It plays important roles in proliferation and apoptosis regulation of certain hepatocellular carcinoma and human breast cancer. Estrogen receptor α (ERα) is involved in the development and progression of human breast cancer. IGF/PI3K/AKT signaling pathway also plays certain roles in the program and regulation of human breast cancer and ovary cancer. However, the biological function of FHL-1 in regulation of human breast cancer and in the cross-talk of estrogen and IGF signaling pathway remains largely unknown. In this paper, we show that FHL-1 protein interacts with ERα and AKT. FHL-1 represses the translation and transcription of estrogen receptor-responsive genes through down-regulating AKT activation. In addition, FHL-1 is not only an ERα-interacting co-regulation protein, but also decreases the phosphorylation of AKT and ERα. Depression of endogenous FHL-1 by FHL-1 targeted small interfering RNA enhances the expression of these proteins and phosphorylation of AKT and ERα. These data suggest that FHL-1 may regulate ER signaling function through regulation of AKT activation besides the physical and functional interaction with ERα. By establishing a linkage role of the FHL-1 between the estrogen ERα signaling pathway and IGF/PI3K/AKT signaling pathway, this study identifies that FHL-1 proteins may be a useful molecular target for human breast cancer therapy.
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