Mena Isoforms: Regulators of the Actin Cytoskeleton and Cell Migration in Breast Cancer Invasion and Metastasis
More than 1 in 3 people will develop cancer in their lifetime, and approximately 1,500 people die from cancer each day. Metastases are the major causes of cancer-related deaths. Key cytoskeletal, proliferative and apoptotic proteins have been shown to dynamically regulate their gene expression during cell invasion and intravasation, suggesting their involvement in regulating some or all of these processes. These proteins have been termed collectively as the "Invasion Signature". One of the components of the "Invasion Signature" is Mena, a member of the Enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) family. Ena/VASP proteins are highly conserved regulators of actin dynamics, known to play critical roles in cell migration. Ena/VASP proteins contain several conserved domains that are thought to elicit specificity of Mena function through alternative splicing. A 19 amino acid exon inserted between the EVH1 domain and the LERER repeats generates a MenaINV isoform. Additionally, a 21 amino acid insertion in the EVH2 domain generates the Mena11a isoform. Expression of the MenaINV isoform sensitizes carcinoma cells to epidermal growth factor (EGF)-induced carcinoma cell invasion and metastasis. In response to lower levels of EGF, expression of Mena INV leads to enhanced metastasis in vivo, and increased invadopodial stability and matrix degradation in vitro. Furthermore, expression of Mena INV results in directional movement of carcinoma cells toward blood vessels and a 200-fold increase in transendothelial migration. Therefore, Mena plays critical roles in metastasis.
Invasion of tumor cells into the surrounding connective tissue and blood vessels is a key step in metastasis of breast tumors. Gene expression profiling of invasive primary mammary tumor cells uncovered four-fold up regulation of mammalian enabled (Mena) mRNA, in a macrophage-dependent microenvironment required for invasion and intravasation. Mena, which is an actin binding protein involved in the regulation of cell motility, has different splice variants such as Mena+, ++, +++, and 11A. These variants are differentially expressed during the progression from non-invasive to metastatic stages of metastatic disease; whereby the Mena+++ variant increases and the Mena11A variant decreases in invasive tumor cells.