Flt-1 Function and Signaling in Breast Cancer

摘要

MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translational repression or RNA degradation. MiR-10b is one miRNA whose expression has been reported to be significantly deregulated in breast cancer. We have identified the VEGF receptor Flt-1 and guanine nucleotide exchange factor (GEF) Tiam1 as targets of miR-10b in breast cancer. We have focused on Tiam1 because it is a positive regulator of cell motility and invasion. Furthermore, Tiam1 expression increases with human breast cancer grade. We report here that downregulation of Tiam1 by miR-10b represses in vitro migration and invasion of breast tumor cells. Tiam1 is a GEF for Rac, a Rho-GTPase that regulates actin dynamics at the leading edge during cell movement. We report that miR-10b-induced downregulation of Tiam1 results in a corresponding decrease in Rac activation, thereby impairing cell motility. The ability of miR-10b to target Tiam1 provides a novel mechanism for regulation of Tiam1 in breast cancer.