title: The WASF3-NCKAP1-CYFIP1 Complex Is Essential for Breast Cancer Metastasis.
abstract: Inactivation of the WASF3 gene suppresses invasion and metastasis of breast cancer cells. WASF3 function is regulated through a protein complex that includes the NCKAP1 and CYFIP1 proteins. Here, we report that silencing NCKAP1 destabilizes the WASF3 complex, resulting in a suppression of the invasive capacity of breast, prostate, and colon cancer cells. In an in vivo model of spontaneous metastasis in immunocompromized mice, loss of NCKAP1 also suppresses metastasis. Activation of the WASF protein complex occurs through interaction with RAC1, and inactivation of NCKAP1 prevents the association of RAC1 with the WASF3 complex. Thus, WASF3 depends on NCKAP1 to promote invasion and metastasis. Here, we show that stapled peptides targeting the interface between NCKAP1 and CYFIP1 destabilize the WASF3 complex and suppress RAC1 binding, thereby suppressing invasion. Using a complex-disrupting compound identified in this study termed WANT3, our results offer a mechanistic proof of concept to target this interaction as a novel approach to inhibit breast cancer metastasis. Cancer Res; 76(17); 5133-42. ©2016 AACR.
authors.affiliation: Department of Oral Biology, Augusta University, Augusta, Georgia. Georgia Cancer Center, Augusta University, Augusta, Georgia. jcowell@augusta.edu ekennedy@uga.edu yteng@augusta.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qin
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Bahassan
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia.
authors.forename: N George
authors.initials: NG
authors.lastname: Bendzunas
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia. jcowell@augusta.edu ekennedy@uga.edu yteng@augusta.edu.
authors.forename: Eileen J
authors.initials: EJ
authors.lastname: Kennedy
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia. jcowell@augusta.edu ekennedy@uga.edu yteng@augusta.edu.
authors.forename: John K
authors.initials: JK
authors.lastname: Cowell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C109916:CYFIP1 protein, human; C484362:NCKAP1 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family