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J Exp Med. 2010 Oct 25;207(11):2421-37. doi: 10.1084/jem.20100433. Epub 2010 Oct 11.

Filamin A regulates focal adhesion disassembly and suppresses breast cancer cell migration and invasion.

Author information

1
Lady Davis Institute for Medical Research, Jewish General Hospital, Faculty of Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada.

Abstract

The actin cross-linking protein filamin A (FLNa) functions as a scaffolding protein and couples cell cytoskeleton to extracellular matrix and integrin receptor signaling. In this study, we report that FLNa suppresses invasion of breast cancer cells and regulates focal adhesion (FA) turnover. Two large progression tissue microarrays from breast cancer patients revealed a significant decrease of FLNa levels in tissues from invasive breast cancer compared with benign disease and in lymph node-positive compared with lymph node-negative breast cancer. In breast cancer cells and orthotopic mouse breast cancer models, down-regulation of FLNa stimulated cancer cell migration, invasion, and metastasis formation. Time-lapse microscopy and biochemical assays after FLNa silencing and rescue with wild-type or mutant protein resistant to calpain cleavage revealed that FLNa regulates FA disassembly at the leading edge of motile cells. Moreover, FLNa down-regulation enhanced calpain activity through the mitogen-activated protein kinase-extracellular signal-regulated kinase cascade and stimulated the cleavage of FA proteins. These results document a regulation of FA dynamics by FLNa in breast cancer cells.

PMID:
20937704
PMCID:
PMC2964581
DOI:
10.1084/jem.20100433
[Indexed for MEDLINE]
Free PMC Article

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