We have also described that human VDR gene is a direct target of SNAIL1 and SNAIL2/ SLUG transcription repressors, and that VDR expression in colon cancer patients is reduced at advanced stages of the disease Palbociclib associated to the upregulation of these factors. Accordingly, high SNAIL1/2 expression in cultured colon cancer cells increases b-catenin transcriptional activity by repressing VDR expression and its Tasocitinib antagonistic activity on Wnt/b-catenin signaling. b-Catenin has a wide range of pleiotropic effects that cannot probably be explained solely by the modulation of TCF/LEF action. Thus, b-catenin has been recently described to bind several transcription factors of the nuclear receptor superfamily and homeobox proteins. In most cases, b-catenin binding enhances the transcriptional activity of these factors and affects the expression of alternative or additional sets of target genes involved in cell-fate decisions along development, tissue homeostasis, or cancer. Our initial description of the direct interaction of b-catenin with VDR in human colon cancer cells has been confirmed in other cell systems. b-catenin/VDR interaction involves the activator function-2 transactivation domain of VDR and the C-terminal domain of b-catenin. In mouse skin, b-catenin/VDR controls target genes, epithelial stem cell fate and tumor development. In this system, increased nuclear b-catenin promoted tumor initiation while VDR ligands protect against cancer by reducing the strength of Wnt/bcatenin signaling. Consistent with this, the treatment of Apcmin/+mice with 1,25 2D3 or analogs reduces tumor load or polyp number and load. It is important to highlight that the level of b-catenin in the nucleus define the strength of the Wnt signal and in consequence the fate or behavior of several types of normal and tumoral cells. In addition to activating mutations of the Wnt/b-catenin pathway components, other genetic alterations like mutations in KRAS or activation of oncogenic pathways like HGF/c-Met signaling enhance nuclear b-catenin accumulation during colon cancer progression. In such scenario, agents able to diminish b-catenin nuclear content and so to attenuate Wnt/b-catenin signal could be potentially used in cancer therapy as long as tumor cells show Wnt pathway addiction. The level of nuclear b-catenin defines the strength of the Wnt/ b-catenin signaling and in consequence the fate and phenotype of many types of normal and cancer cells.