Abstract
Vitamin D receptor (VDR) can modulate functionally antagonistic growth regulatory pathways, involving β‐catenin/E‐cadherin on one hand and osteopontin (OPN) on the other. This study investigates effects of VDR ligand treatment on the balance of these discordant signals and on associated cell behavior. Treatment of Rama 37 or SW480 cells by 1α,25‐(OH)~2~ D~3~ or analogs suppressed β‐catenin/Lef‐1/Tcf signaling and upregulated E‐cadherin, consistent with a cancer‐inhibitory action. Conversely, treatment also increased transcription of OPN that may be implicated in tumor progression. Molecular crosstalk was observed between the antagonistic VDR‐dependent signals, in that β‐catenin/Lef‐1/Tcf molecules modulated VDR activation of OPN. Treatment effects on cell growth were related to a constitutive balance of OPN and E‐cadherin expression. No growth effects were observed in Rama 37 cells that have low OPN and high E‐cadherin expression. Conversely, treatment of Rama 37 stably transfected subclones that had high OPN and/or low level E‐cadherin induced small but significant increases of cell attachment to fibronectin, anchorage‐independent growth or invasion. This study shows that relative expression levels of key VDR downstream genes may influence growth regulation by 1α,25‐(OH)~2~ D~3~ or analogs. These findings may be relevant to the cell‐ or tissue‐specificity of vitamin D growth regulation. © 2009 Wiley‐Liss, Inc.