Abstract
Pet dogs very frequently develop spontaneous mammary tumors and have been suggested as a good model organism for breast cancer research. In order to obtain an insight into underlying signaling mechanisms during canine mammary tumorigenesis, in this study we assessed the incidence and the mechanism of canonical Wnt activation in a panel of 12 canine mammary tumor cell lines. We show that a subset of canine mammary cell lines exhibit a moderate canonical Wnt activity that is dependent on Wnt ligands, similar to what has been described in human breast cancer cell lines. In addition, three of the tested canine mammary cell lines have a high canonical Wnt activity that is not responsive to inhibitors of Wnt ligand secretion. Tumor cell lines with highly active canonical Wnt signaling often carry mutations in key members of the Wnt signaling cascade. These cell lines, however, carry no mutations in the coding regions of intracellular Wnt pathway components (APC, β-catenin, GSK3β, CK1α and Axin1) and have a functional β-catenin destruction complex. Interestingly, however, the cell lines with high canonical Wnt activity specifically overexpress LEF1 mRNA and the knock-down of LEF1 significantly inhibits TCF-reporter activity. In addition, LEF1 is overexpressed in a subset of canine mammary carcinomas, implicating LEF1 in ligand-independent activation of canonical Wnt signaling in canine mammary tumors. We conclude that canonical Wnt activation may be a frequent event in canine mammary tumors both through Wnt ligand-dependent and novel ligand–independent mechanisms.
Highlights
The Wnt signaling is one of the key players during normal mammary gland development as well as during mammary tumorigenesis [1]
This triggers Dishevelled-dependent disruption of the b-catenin-destruction complex in the cytoplasm that is composed of multiple proteins including, glycogen synthase kinase 3b (GSK3b), adenomatous polyposis coli (APC), Axin1 and casein kinase 1 (CK1)
Stabilized b-catenin translocates to the nucleus where it can associate with the T-cell factor (TCF)/Lymphoid enhancer-binding factor (LEF)-family of transcription factors to regulate the expression of specific target genes
Summary
The Wnt signaling is one of the key players during normal mammary gland development as well as during mammary tumorigenesis [1]. The canonical, b-catenin-mediated Wnt signaling is activated by secreted Wnt ligands through activation of transmembrane frizzled (Fzd) receptors and LDL-receptor related protein 5 or 6 (Lpr5/6) co-receptors. Many studies have documented active Wnt signaling in mammary tissue based on presence of stabilized b-catenin protein and often in combination with aberrant expression of target genes (e.g. Axin). Many studies have documented active Wnt signaling in mammary tissue based on presence of stabilized b-catenin protein and often in combination with aberrant expression of target genes (e.g. Axin2) Based on these criteria, over 50% of human breast tumor tissue samples assessed, showed signs of aberrant canonical Wnt activity (reviewed in [3]). A number of studies showed that the effect of
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