Four-and-a-half-LIM protein 1 down-regulates estrogen receptor a. activity through repression of AKT phosphorylation in human breast cancer cell

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 a (ER alpha) 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 ERa and AKT. FHL-1 represses the translation and transcription of estrogen receptor-responsive genes through down-regulating ART activation. In addition, FHL-1 is not only an ER alpha-interacting co-regulation protein, but also decreases the phosphorylation of ART and ERa. Depression of endogenous FHL-1 by FHL-1 targeted small interfering RNA enhances the expression of these proteins and phosphorylation of Ala and ERa. These data suggest that FHL-1 may regulate ER signaling function through regulation of ART activation besides the physical and functional interaction with ERa. By establishing a linkage role of the FHL-1 between the estrogen ERa 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. (C) 2011 Elsevier Ltd. All rights reserved.