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

David J. Mulholland, Shoukat Dedhar, Gerhard A. Coetzee, Colleen C. Nelson

Research output: Contribution to journalReview articlepeer-review

354 Scopus citations


The cross-regulation of Wnt/β-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/β-catenin modulation of NRs (theme I), and ligand-dependent NR inhibition of the Wnt/β-catenin/Tcf cascade (theme II). β-Catenin, a promiscuous Wnt signaling member, has been studied intensively in relation to the androgen receptor (AR). β-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 β-catenin and AR, engages in a dynamic reciprocity of nuclear β-catenin, p300/CREB binding protein, and transcriptional initiation factor 2/GC receptor-interaction protein, thereby facilitating hormone-dependent coactivation and transrepression. β-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 D3, trans/cis RA, glucocorticoids, and thiazolidines, induce dramatic changes in the physiology of cells harboring high Wnt/β-catenin/Tcf activity. Wnt signaling regulates, directly or indirectly, developmental processes such as ductal branching and adipogenesis, two processes dependent on NR function. β-Catenin has been intensively studied in colorectal cancer; however, it is now evident that β-catenin may be important in cancers of the breast, prostate, and thyroid. This review will focus on the cross-regulation of AR and Wnt/β-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/β-catenin signaling pathway, striking cell line and tissue-specific differences require deciphering and application to endocrine pathology.

Original languageEnglish
Pages (from-to)898-915
Number of pages18
JournalEndocrine Reviews
Issue number7
StatePublished - Dec 2005
Externally publishedYes


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