Inhibition of SHIP2 activity inhibits cell migration and could prevent metastasis in breast cancer cells

Abstract

Metastasis of breast cancer cells to distant organs is responsible for approximately 50 % in cancer related deaths in women worldwide. SHIP2 is a phosphoinositide 5-phosphatase for PI(3,4,5)P3 and PI(4,5)P2. Through depletion of SHIP2 in triple negative MDA-MB-231 cells and the use of SHIP2 inhibitors, it appeared that cell migration is positively controlled by SHIP2. The effect of SHIP2 on migration, observed in MDA-MB-231 cells, appears to be mediated by PI(3,4)P2. Adhesion on fibronectin is always increased in SHIP2 depleted cells. Apoptosis measured in MDA-MB-231 cells is also increased in SHIP2 depleted cells as compared to control cells. In xenograft mice, SHIP2 depleted MDA-MB-231 cells form significantly smaller tumors compared to control cells and less metastasis detected in lung sections. Our data reveal a general role of SHIP2 in the control of cell migration in breast cancer cells and a second messenger role for PI(3,4)P2 in the migration mechanism. In this model, SHIP2 function on apoptosis on cells incubated in vitro, or in mice tumor digested cells, could account for its role on tumor growth determined in vivo.