The cofilin pathway in breast cancer invasion and metastasis

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Abstract
A pattern of changes in gene expression clustered in the cofilin pathway is consistently observed in mammary tumours and cells derived from them. The cofilin pathway has emerged as having a central role in the generation of free actin filament ends resulting in actin filament remodelling by polymerization and depolymerization. Filament remodelling is essential during the formation and retraction of path-finding structures used in the chemotaxis, cell migration and invasion of tumour cells. The spatial localization of cofilin activity is required for chemotaxis by tumour cells in response to epidermal growth factor, and fits a local excitation global inhibition (LEGI)-type model of chemotaxis. A balance of the stimulatory and inhibitory branches of the cofilin pathway must be achieved for protrusion, cell migration and chemotaxis to occur optimally. Too much or too little activity will inhibit all of these essential steps in motility and invasion. As there are four regulatory mechanisms for cofilin activity which seem to be uncoupled, the activity status of cofilin in a cell cannot be assessed by measuring the ratio of dephosphorylated cofilin to the total cofilin present. An important implication of recent studies of the cofilin pathway is that looking at the expression status of a single gene can be misleading when interpreting phenotype, as it is the collective activity of multiple genes of the pathway that determines the integrated output of the pathway and therefore phenotype. The rational design of inhibitors of the cofilin pathway is possible. Measuring the output of the cofilin pathway directly in living cells isolated from invasive tumours will be necessary to assess the efficacy of the inhibitors. New technologies for intravital imaging, invasive tumour cell collection and expression profiling, and for measuring cofilin pathway activity, make inhibitor design and testing possible.