title: The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling.
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 reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize 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, colonization, 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 remodeling 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 remodeling 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. Cancer Res; 76(14); 4236-48. ©2016 AACR.
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia. Mariam.mansour@petermac.org.
authors.forename: Mariam
authors.initials: M
authors.lastname: Mansour
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Sue
authors.initials: S
authors.lastname: Haupt
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Ai-Leen
authors.initials: AL
authors.lastname: Chan
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Godde
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rizzitelli
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Franco
authors.initials: F
authors.lastname: Caramia
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Deb
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Takano
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Bishton
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
authors.forename: Cameron
authors.initials: C
authors.lastname: Johnstone
authors.affiliation: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Brendon
authors.initials: B
authors.lastname: Monahan
authors.affiliation: Lautenberg Centre, Hebrew University, Jerusalem, Israel.
authors.forename: Yarra
authors.initials: Y
authors.lastname: Levav-Cohen
authors.affiliation: Division of Medical Genetics, Department of Pediatrics and Neurobiology, Duke University, Durham, North Carolina.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
authors.affiliation: Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Alpha S
authors.initials: AS
authors.lastname: Yap
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fox
authors.affiliation: St. Vincent's Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Ora
authors.initials: O
authors.lastname: Bernard
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia.
authors.forename: Robin
authors.initials: R
authors.lastname: Anderson
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Ygal
authors.initials: Y
authors.lastname: Haupt
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000502:physiology*
chemical_list: C489850:ECT2 protein, human; D011518:Proto-Oncogene Proteins; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D020741:rho GTP-Binding Proteins