E3 ligase E6AP represses breast cancer metastasis via regulation of ECT2-Rho signalling
- Mansour, M; Haupt, S; Chan, AL; Godde, N; Rizzitelli, A; Loi, S; Caramia, F; Deb, S; Takano, EA; Bishton, M; Johnstone, CN; Monahan, B; Levav-Cohen, Y; Jiang, YH; Yap, AS; Fox, SB; Bernard, O; Anderson, RL; Haupt, Y;
- Journal Title
- Cancer Res
- Publication Type
- Journal Article in press
- 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 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.
- WEHI Research Division(s)
- Systems Biology And Personalised Medicine
- PubMed ID
- Publisher's Version
- Refer to copyright notice on published article.
Creation Date: 2016-06-16 12:25:11Last Modified: 2017-08-24 11:41:39