b-catenin is a multifunctional adaptor protein/transcription factor that is deregulated in many cancers. In the absence of Wnt ligand, cytosolic b-catenin levels are down-regulated via a degradation complex including CK1a, GSK3b, Axin, APC, and PP2A in which processive phosphorylation of b-catenin by CK1a and GSK3b leads to its ubiquitination and proteasomal degradation. In the presence of Wnt ligand, upon its binding to the frizzled/LRP5/6 receptor complex, Dishevelled is activated, at least in part by phosphorylation. Allowing the dephosphorylation and nuclear import of b-catenin, where it activates the TCF/LEF family of transcriptional CYT 11387 factors that control expression of various genes related to cell cycle and differentiation. Wnt/b-catenin pathway is strongly implicated in breast carcinogenesis, in addition to many other cancer types. Transgenic mice expressing degradation-resistant b-catenin in mammary gland tissue develop breast tumors. According to immunohistochemical analysis, nuclear and cytoplasmic b-catenin levels have been found to be elevated in about 60% of the breast tumors. Furthermore, reduced levels of extracellular Wnt-inhibitory molecules sFRP1 and WIF1 have been linked to 80% and 60% of breast carcinomas. Additionally, b-catenin has been associated with epidermal growth factor receptor family members and the stability of b-catenin and its TCF/LEFactivating function has been suggested to be regulated via tyrosine phosphorylation by the EGFR family, which may be significant for breast carcinogenesis, since human epidermal growth factor receptor 2 is overexpressed in about 30% of human breast tumors. Hence, identification of novel targets of Wnt/b-catenin pathway, serves an important purpose for cancer research field, particularly breast cancer, since target genes of the pathway are potential anti-cancer drug targets. Many actin-associated proteins play important roles in carcinogenesis of various types of cancers. MENA is an actinregulatory protein that belongs to ENA/VASP protein family. Members of this protein family are localized at the tips of protruding lamellipodia and filopodia and adhesion foci; and they are involved in control of cell motility and cell-cell adhesion, which are important subjects for development of metastatic potential. Di Modugno et al. showed that human MENA is overexpressed in,75% of primary breast cancers. In our previous study, we employed SAGE and genome-wide microarray approaches to screen for novel Wnt/b-catenin pathway targets by overexpressing degradation-resistant S33Y-b-catenin in Huh7 cell lines, which lacks detectable nuclear endogenous b-catenin levels. In these screens we found MENA to be differentially expressed and in this study we show that MENA is a transcriptional target of the Wnt/b-catenin pathway. Wnt and Notch pathways have essential roles in development with well-studied crosstalks, yet their interplay in cancer is not well understood. In order to investigate the role of MENA in tumorigenesis, we tested whether knock-down of the Drosophila homolog of MENA can affect tumor formation in the D. melanogaster eye cancer fly models “eyeful” and “sensitized”. Eyeful flies have a metastatic eye tumor phenotype induced by activated Notch signalling due to overexpression of the Notch ligand Delta and overexpression of polycomb genes lola and pipsqueak.