Knockdown of Abl interactor 1 expression impairs invadopodia formation, tumor angiogenesis, and markedly slows tumor growth of breast cancer cells.

Abstract

Abstract Abstract #2054 Background: Abl interactor 1 (Abi1) is a key regulator of actin polymerization/depolymerization. Previous studies have revealed that Abi1 interacts with Wiskott–Aldrich syndrome protein (Wasp) family proteins, and regulates the nucleation promoting activity of Wasp proteins. In addition to Wasp family proteins, Abi1 also binds to a variety of other signaling molecules, including those involved in the signal transductions of small GTP-binding protein Rac and PI3 kinase. The ability to interact with diverse signaling pathways places Abi1 at a central position in the signaling network that regulates cell motility and proliferation. The involvement of Abi1 in the development of abnormal cytoskeletal functions of cancer cells has recently been reported. It remains unclear, however, how Abi1 exerts its effects in tumor cells and whether it contributes to tumor progression in vivo.
 Material and Methods: The short hairpin RNA (shRNA)-mediated gene silencing was used, in conjunction with murine tumor xenograft models, to examine the effects of Abi1 knockdown on cytoskeleton remodeling, cell migration, invasion, as well as tumor growth and angiogenesis of MDA-MB231 breast cancer cells.
 Results: We report here a novel function for Abi1 in the regulation of invadopodia formation as well as in the tumor angiogenesis and invasion of breast cancer cells, possibly through the modulation of Src and matrix metalloproteinase 9 (MMP-9) activities. Abi1 co-localizes with invadopodia, the specialized adhesive/invasive structures believed to control the invasion of tumor cells, in MDA-MB231 breast cancer cells. Epigenetic silencing of the Abi1 gene by shRNA in MDA-MB231 cells impaired the formation of invadopodia and decreased the activity of c-Src and MMP-9. The decreased invadopodia formation and MMP-9 activity correlated with a reduction in the ability of these cells to degrade extracellular matrix (ECM). Remarkably, the knockdown of Abi1 expression inhibited tumor invasion and angiogenesis and markedly slowed tumor growth in xenograft mouse models. Taken together, these results indicate that the Abi1 signaling plays a critical role in breast cancer progression and suggest that this pathway may serve as a therapeutic target for the treatment of human breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2054.