Breast Cancer Awareness: Cdc42-Interacting Protein 4 Promotes Breast Cancer Cell Invasion and Formation of Invadopodia through Activation of N-WASp

Cdc42-Interacting Protein 4 Promotes Breast Cancer Cell Invasion and Formation of Invadopodia through Activation of N-WASp — Cancer Res

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Cdc42-Interacting Protein 4 Promotes Breast Cancer Cell Invasion and Formation of Invadopodia through Activation of N-WASp Christina S. Pichot 1, Constadina Arvanitis 3, Sean M. Hartig 2, Samuel A. Jensen 3, John Bechill 3, Saad Marzouk 3, Jindan Yu 4, Jeffrey A. Frost 1, and Seth J. Corey 3

Authors' Affiliations:1Integrative Biology and Pharmacology, University of Texas Health Science Center; 2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas and 3Departments of Pediatrics and Cellular and Molecular Biology, Children's Memorial Hospital and the Robert H. Lurie Comprehensive Cancer Center and 4Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois Corresponding Author:
Seth J. Corey, Robert H. Lurie Comprehensive Cancer Center, 303 East Superior Street, Chicago, IL 60611. Phone: 312-503-6694; Fax: 312-503-0189; E-mail: s-corey{at}northwestern.edu. Abstract In the earliest stages of metastasis, breast cancer cells must reorganize the cytoskeleton to affect cell shape change and promote cell invasion and motility. These events require the cytoskeletal regulators Cdc42 and Rho, their effectors such as N-WASp/WAVE, and direct inducers of actin polymerization such as Arp2/3. Little consideration has been given to molecules that shape the cell membrane. The F-BAR proteins CIP4, TOCA-1, and FBP17 generate membrane curvature and act as scaffolding proteins for activated Cdc42 and N-WASp. We found that expression of CIP4, but not TOCA-1 or FBP17, was increased in invasive breast cancer cell lines in comparison with weakly or noninvasive breast cancer cell lines. Endogenous CIP4 localized to the leading edge of migrating cells and to invadopodia in cells invading gelatin. Because CIP4 serves as a scaffolding protein for Cdc42, Src, and N-WASp, we tested whether loss of CIP4 could result in decreased N-WASp function. Interaction between CIP4 and N-WASp was epidermal growth factor responsive, and CIP4 silencing by small interfering RNA caused decreased tyrosine phosphorylation of N-WASp at a Src-dependent activation site (Y256). CIP4 silencing also impaired the migration and invasion of MDA-MB-231 cells and was associated with decreased 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.

Footnotes Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).