hway in Mammary Epithelial and Cancer Cells

nloaded ough Wnt1 downstream signaling components as well as cytoplasmic level of metastatic tumor antishort form (MTA1s) are elevated in human breast cancer, it remains unknown whether a regulatory talk exists between these two pathways. Here, we provide evidence of a remarkable correlation bethe levels of MTA1s and stimulation of the Wnt1 signaling components, leading to increased stabin of β-catenin and stimulation of Wnt1 target genes in the murine mammary epithelial and human cancer cells. We found that MTA1s influences Wnt1 pathway through extracellular signal-regulated (ERK) signaling as selective silencing of the endogenous MTA1s or ERK, or its target glycogen se kinase 3β resulted in a substantial decrease in β-catenin expression, leading to the inhibition of target genes. Furthermore, downregulation of β-catenin in cells with elevated MTA1s level was accomby a corresponding decrease in the expression of Wnt1 target genes, establishing a mechanistic role ERK/glycogen synthase kinase 3β/β-catenin pathway in the stimulation of the Wnt1 target genes by s in mammary epithelial cells. In addition, mammary glands from the virgin MTA1s transgenic mice ked the phenotypic changes found in the Wnt1 transgenic mice and exhibited an overall hyperactivaf the Wnt1 signaling pathway, leading to increased stabilization and nuclear accumulation of nin. Mammary glands from the virgin MTA1s-TG mice revealed ductal hyperplasia and ductal oma in situ, and low incidence of palpable tumors. These findings reveal a previously unrecognized carcin role for MTA1s as an important modifier of the Wnt1 signaling in mammary epithelial and cancer cells. Cancer Res; 70(16); 6598–608. ©2010 AACR.