title: A novel role for BRCA1 in regulating breast cancer cell spreading and motility.
abstract: BRCA1 C-terminal (BRCT) domains in BRCA1 are essential for tumor suppressor function, though the underlying mechanisms remain unclear. We identified ezrin, radixin, and moesin as BRCA1 BRCT domain-interacting proteins. Ezrin-radixin-moesin (ERM) and F-actin colocalized with BRCA1 at the plasma membrane (PM) of cancer cells, especially at leading edges and focal adhesion sites. In stably expressing cancer cells, high levels of enhanced green fluorescent protein (EGFP)-BRCA1(1634-1863) acted as a dominant-negative factor, displacing endogenous BRCA1 from the PM. This led to delayed cell spreading, increased spontaneous motility, and irregular monolayer wound healing. MCF-7 cells (intact BRCA1) showed lower motility than HCC1937 cells (truncated BRCA1), but expression of EGFP-BRCA1(1634-1863) in MCF-7 increased motility. Conversely, full-length BRCA1 expression in HCC1937 decreased motility but only if the protein retained ubiquitin ligase activity. We conclude that full-length BRCA1 is important for complete tumor suppressor activity via interaction of its BRCT domains with ERM at the PM, controlling spreading and motility of cancer cells via ubiquitin ligase activity.
authors.affiliation: Department of Pathology, University of Ghent, 9000 Ghent, Belgium.
authors.forename: Elisabeth D
authors.initials: ED
authors.lastname: Coene
authors.forename: Catarina
authors.initials: C
authors.lastname: Gadelha
authors.forename: Nicholas
authors.initials: N
authors.lastname: White
authors.forename: Ashraf
authors.initials: A
authors.lastname: Malhas
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thomas
authors.forename: Michael
authors.initials: M
authors.lastname: Shaw
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaux
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006367:HeLa Cells; D006801:Humans; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D019313:BRCA1 Protein; D044767:Ubiquitin-Protein Ligases