The WASF3–NCKAP1–CYFIP1 Complex Is Essential for Breast Cancer Metastasis
- 31 August 2016
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 76 (17), 5133-5142
- https://doi.org/10.1158/0008-5472.can-16-0562
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.Keywords
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Funding Information
- National Institutes of Health (CA120510)
- National Institutes of Health (CA188439)
- Department of Defense (W81XWH-14-1-0412)
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