Interaction of nuclear receptors with the Wnt/β-catenin/Tcf signaling axis:: Wnt you like to know?

The cross- regulation of Wnt/beta-catenin/ Tcf ligands, kinases, and transcription factors with members of the nuclear receptor ( NR) family has emerged as a clinically and developmentally important area of endocrine cell biology. Interactions between these signaling pathways result in a diverse array of cellular effects including altered cellular adhesion, tissue morphogenesis, and oncogenesis. Analyses of NR interactions with canonical Wnt signaling reveal two broad themes: Wnt/beta- catenin modulation of NRs ( theme I), and ligand-dependent NR inhibition of the Wnt/beta- catenin/ Tcf cascade ( theme II). beta- Catenin, a promiscuous Wnt signaling member, has been studied intensively in relation to the androgen receptor ( AR). beta- Catenin acts as a coactivator of AR transcription and is also involved in cotrafficking, increasing cell proliferation, and prostate pathogenesis. T cell factor, a transcriptional mediator of beta- catenin and AR, engages in a dynamic reciprocity of nuclear beta- catenin, p300/ CREB binding protein, and transcriptional initiation factor 2/ GC receptor-interaction protein, thereby facilitating hormone- dependent coactivation and transrepression. beta- Catenin responds in an equally dynamic manner with other NRs, including the retinoic acid ( RA) receptor ( RAR), vitamin D receptor ( VDR), glucocorticoid receptor ( GR), progesterone receptor, thyroid receptor ( TR), estrogen receptor ( ER), and peroxisome proliferator- activated receptor ( PPAR). The NR ligands, vitamin D-3, trans/ cis RA, glucocorticoids, and thiazolidines, induce dramatic changes in the physiology of cells harboring high Wnt/ beta- catenin/ Tcf activity. Wnt signaling regulates, directly or indirectly, developmental processes such as ductal branching and adipogenesis, two processes dependent on NR function. beta- Catenin has been intensively studied in colorectal cancer; however, it is now evident that beta- catenin may be important in cancers of the breast, prostate, and thyroid. This review will focus on the cross- regulation of AR and Wnt/ beta-catenin/ Tcf but will also consider the dynamic manner in which RAR/ RXR, GR, TR, VDR, ER, and PPAR modulate canonical Wnt signaling. Although many commonalities exist by which NRs interact with the Wnt/ beta- catenin signaling pathway, striking cell line and tissue- specific differences require deciphering and application to endocrine pathology.