The Wnt signaling pathways are initiated by the binding of the Wnt ligand to the Fz receptor.  There are three different molecular pathways downstream of the Wnt/Fz interaction.  The majority of research has focused on the Wnt/β-catenin pathway (also known as the "canonical" Wnt pathway), which manages cell fate determination by regulating gene expression.  The Wnt/Ca and Wnt/polarity pathways are known as the "non-canonical pathways".  The decision of which pathway is activated most likely depends on which Wnt ligand and Fz receptor are present, as well as the cellular context.  Nineteen Wnt ligands and ten different members of the Fz seven-transmembrane receptor family have been described in the human genome.  As a result, a large variety of responses could be initiated from the Wnt/Fz interactions.
The Wnt/β-catenin pathway starts with the binding of Wnt to a receptor complex encompassing a Fz receptor and LRP co-receptor.  After Wnt binds, an intracellular protein named Dishevelled (Dvl) is activated via phosphorylation. β-catenin degradation complexes in the cytoplasm are composed of adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β) and Axin.  APC promotes the degradation of β-catenin by increasing the affinity of the degradation complex to β-catenin.  Axin is a scaffolding protein which holds the degradation complex together.  The activated Dvl associates with Axin and prevents GSK3β and casein kinase 1α (CK1α) from phosphorylating critical substrates, such as β-catenin.  Phosphorylation of β-catenin marks the protein for ubiquitylation and rapid degradation by proteasomes.  Thus, the binding of Wnt to the receptor results in a non-phosphorylated form of β-catenin which localizes to the nucleus and, after displacing the Groucho corepressor protein, forms a complex with Tcf/Lef transcription factors and co-activators (such as CREB binding protein) and induces the expression of downstream target genes.
β-catenin is actively stabilized in over 50% of breast cancers and its nuclear localization correlates with poor patient prognosis.  Several target genes of the Wnt signaling pathway, such as cyclin D1, are activated in a significant proportion of breast tumours. It has been shown that SFRP1 transcription can be driven by B-catenin in normal intestinal epithelial cells.  Neoplastic epithelial cells were treated with lithium chloride, which inhibits GSK3B and thus stabilizes B-catenin.  Lithium chloride is widely used to mimic Wnt signaling.  Rather than suppressing SFRP1 expression, B-catenin/TCF activity was associated with the induction of SFRP1.  This is consistent with a negative feedback response restricting the exposure of a normal cell to a prolonged Wnt growth factor signal.
Hedgehog signaling in the intestinal epithelium represses the canonical Wnt signaling to restrict expression of Wnt target genes to stem or progenitor cells.  It was thought that the Hedgehog signaling pathway does this via the induction of the secreted-type Wnt inhibitor.  Katoh et al. searched for the GLI-binding site within the promoter region of Wnt inhibitor genes.  GLI are transcription factors that activate the transcription of Hedgehog target genes.  The GLI-binding site was identified within the 5’-flanking promoter region of the human SFRP1 gene.  The GLI-binding site was conserved among promoter regions of mammalian SFRP1 orthologs.  These facts indicate that the SFRP1 gene was identified as the evolutionarily conserved target of the Hedgehog-GLI signaling pathway.  SFRP1 was found to be expressed in mesenchymal cells.  Hedgehog is secreted from differentiated epithelial cells to induce SFRP1 expression in mesenchymal cells, which keeps differentiated epithelial cells away from the effect of canonical Wnt signaling.  Thus, SFRP1 is most likely the Hedgehog target to confine canonical Wnt signaling within stem or progenitor cells.  Epigenetic CpG hypermethylation of the SFRP1 promoter during chronic persistent inflammation and aging leads to the occurrence of gastrointestinal cancers, such as colorectal cancer and gastric cancer, through the breakdown of Hedgehog-dependent Wnt signal inhibition.