Abstract A72: The E3-ligase E6AP represses breast cancer metastasis through regulation of ECT2-Rho-GTPases signaling

Abstract

Abstract Metastatic disease is the major cause of breast cancer related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganisation, to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonise distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonisation and metastasis in mice and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for with basal breast cancer. E6AP regulates actin cytoskeletal remodelling via regulation of Rho-GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho-GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodelling through the control of ECT2 and Rho-GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer. Note: This abstract was not presented at the conference. Citation Format: Mariam Mansour, Sue Haupt, Ai-Leen Chan, Nathan Godde, Alexandra Rizzitelli, Sherene Loi, Franco Caramia, Siddartha Deb, Elena A. Takano, Mark Bishton, Cameron Johnstone, Yarra Levav-Cohen, Yong-Hui Jiang, Alpha S. Yap, Stephen Fox, Ora Bernard, Robin Anderson, Ygal Haupt. The E3-ligase E6AP represses breast cancer metastasis through regulation of ECT2-Rho-GTPases signaling. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A72.