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The motility pathways identified in the Invasion Signature converge on the Cofilin/Mena pathway identifying it as a master regulator of chemotaxis, invasion and dissemination of breast tumor cells in vivo. Using markers derived from the Cofilin/Mena pathway, anatomical landmarks have been developed for use with breast cancer patients. One of these, composed of an invading carcinoma cell marked by Mena over-expression, and a peri-vascular macrophage, is called TMEM (Tumor MicroEnvironment for Metastasis) in human breast tumors. Another is cofilin x P-cofilin, a marker of activation of the Cofilin/Mena pathway in tumor cells. TMEM density and cofilin x P-cofilin intensity are each predictors of metastatic risk in human invasive ductal carcinomas of the breast. An important clue as to mechanism relating the Cofilin/Mena pathway to metastasis is the finding that migrating tumor cells in vivo exhibit alternative splicing of Mena resulting in increased expression of MenaINV isoform and decreased expression of Mena11a isoform. Furthermore, MenaINV enhances the sensitivity of EGFR in tumor cells to EGF by 50 fold and increases paracrine signaling with macrophages while Mena 11a decreases EGF sensitivity and CSF1 synthesis in tumor cells dramatically decreasing paracrine signaling with macrophages. The consequences of increased sensitivity of EGFR are profound resulting in increased tumor cell chemotaxis, streaming migration, dissemination and metastasis in vivo in mouse mammary tumors. An underlying molecular mechanism by which MenaINV increases
EGFR sensitivity to EGF is its ability to activate EGFR to stimulate PLCgamma
to activate cofilin. This creates new actin polymerization at the plasma
membrane. Hence, MenaINV results in increased Cofilin-mediated
chemotaxis toward macrophages and macrophage-mediated transendothelial
migration.
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