Cdc42-interacting protein 4 promotes breast cancer cell invasion and formation of invadopodia through activation of N-WASp.

acrjourna he earliest stages of metastasis, breast cancer cells must reorganize the cytoskeleton to affect cell shape e and promote cell invasion and motility. These events require the cytoskeletal regulators Cdc42 and heir effectors such as N-WASp/WAVE, and direct inducers of actin polymerization such as Arp2/3. Little eration has been given to molecules that shape the cell membrane. The F-BAR proteins CIP4, TOCA-1, P17 generate membrane curvature and act as scaffolding proteins for activated Cdc42 and N-WASp. We that expression of CIP4, but not TOCA-1 or FBP17, was increased in invasive breast cancer cell lines in rison with weakly or noninvasive breast cancer cell lines. Endogenous CIP4 localized to the leading edge rating cells and to invadopodia in cells invading gelatin. Because CIP4 serves as a scaffolding protein c42, Src, and N-WASp, we tested whether loss of CIP4 could result in decreased N-WASp function. ction between CIP4 and N-WASp was epidermal growth factor responsive, and CIP4 silencing by small ring RNA caused decreased tyrosine phosphorylation of N-WASp at a Src-dependent activation site . CIP4 silencing also impaired the migration and invasion of MDA-MB-231 cells and was associated with sed formation of invadopodia and gelatin degradation. This study presents a new role for CIP4 in the promotion of migration and invasion of MDA-MB-231 breast cancer cells and establishes the contribution of F-BAR proteins to cancer cell motility and invasion. Cancer Res; 70(21); 8347–56. ©2010 AACR.