A novel role for BRCA1 in regulating breast cancer cell spreading and motility

Department of Pathology, University of Ghent, 9000 Ghent, Belgium.
The Journal of Cell Biology (Impact Factor: 9.83). 02/2011; 192(3):497-512. DOI: 10.1083/jcb.201004136
Source: PubMed


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.

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    • "2A and B (right), with exception for BRCA1 in hypoxic BMSCs). Since BRCA1 was recently implicated in the adhesion, spreading, and motility of breast cancer cells by interaction with F-actin and the ezrin/ radixin/moesin complex (Coene et al., 2011), it thus seems plausible that this gene together with RAD51, may also play an important role in the adhesion of SCs to culture-treated plastic. Prolonged passaging in normoxia led to a significant down-regulation of Ku80 and BRCA1 in BMSCs, and RAD51 and BRCA1 in ASCs. "
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