ABSTRACT
Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.
Subject(s)
Receptors, Cytoplasmic and Nuclear/metabolism , Signal Transduction/physiology , Wnt Proteins/metabolism , Animals , Cell Membrane/metabolism , Cell Nucleus/metabolism , Extracellular Space/metabolism , Humans , In Vitro Techniques , Male , Models, Biological , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Receptor Cross-Talk , Receptors, Androgen/metabolism , beta Catenin/metabolismABSTRACT
BACKGROUND: The vitamin D receptor (VDR) pathway is important in the prevention and potentially in the treatment of many cancers. One important mechanism of VDR action is related to its interaction with the Wnt/beta-catenin pathway. Agonist-bound VDR inhibits the oncogenic Wnt/beta-catenin/TCF pathway by interacting directly with beta-catenin and in some cells by increasing cadherin expression which, in turn, recruits beta-catenin to the membrane. Here we identify TCF-4, a transcriptional regulator and beta-catenin binding partner as an indirect target of the VDR pathway. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we show that TCF-4 (gene name TCF7L2) is decreased in the mammary gland of the VDR knockout mouse as compared to the wild-type mouse. Furthermore, we show 1,25(OH)2D3 increases TCF-4 at the RNA and protein levels in several human colorectal cancer cell lines, the effect of which is completely dependent on the VDR. In silico analysis of the human and mouse TCF7L2 promoters identified several putative VDR binding elements. Although TCF7L2 promoter reporters responded to exogenous VDR, and 1,25(OH)2D3, mutation analysis and chromatin immunoprecipitation assays, showed that the increase in TCF7L2 did not require recruitment of the VDR to the identified elements and indicates that the regulation by VDR is indirect. This is further confirmed by the requirement of de novo protein synthesis for this up-regulation. CONCLUSIONS/SIGNIFICANCE: Although it is generally assumed that binding of beta-catenin to members of the TCF/LEF family is cancer-promoting, recent studies have indicated that TCF-4 functions instead as a transcriptional repressor that restricts breast and colorectal cancer cell growth. Consequently, we conclude that the 1,25(OH)2D3/VDR-mediated increase in TCF-4 may have a protective role in colon cancer as well as diabetes and Crohn's disease.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/biosynthesis , Colorectal Neoplasms/metabolism , Gene Expression Regulation , Mammary Glands, Animal/metabolism , Receptors, Calcitriol/metabolism , Transcription Factors/biosynthesis , Vitamin D/metabolism , Animals , Caco-2 Cells , Cadherins/metabolism , Cell Line, Tumor , Humans , Mice , Mice, Knockout , Promoter Regions, Genetic , Transcription Factor 4 , Wnt Proteins/metabolism , beta Catenin/metabolismABSTRACT
Mouse mammary tumors arising during medroxyprogesterone-DMBA-mediated mammary carcinogenesis comprised three distinct phenotypes: adenocarcinoma, squamous cell carcinoma, and myoepithelial carcinoma. The molecular signature for each of the three tumor subsets was characterized by gene microarray analysis, and three distinct sets of gene expression profiles were obtained that were corroborated in part by quantitative RT-PCR and immunohistochemistry. These results suggest that this carcinogenesis and gene expression model will be useful for rapidly assessing the histopathological differences arising in mammary carcinogenesis and the effects of tumor promoting or chemoprevention agents.
