Control of TCF-4 expression by VDR and vitamin D in the mouse mammary gland and colorectal cancer cell lines.

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.

The molecular basis of vitamin D receptor and beta-catenin crossregulation.

The signaling/oncogenic activity of beta-catenin can be repressed by activation of the vitamin D receptor (VDR). Conversely, high levels of beta-catenin can potentiate the transcriptional activity of 1,25-dihydroxyvitamin D3 (1,25D). We show here that the effects of beta-catenin on VDR activity are due to interaction between the activator function-2 (AF-2) domain of the VDR and C terminus of beta-catenin.

Cyclin D1 genetic heterozygosity regulates colonic epithelial cell differentiation and tumor number in ApcMin mice.

Constitutive beta-catenin/Tcf activity, the primary transforming events in colorectal carcinoma, occurs through induction of the Wnt pathway or APC gene mutations that cause familial adenomatous polyposis. Mice carrying Apc mutations in their germ line (ApcMin) develop intestinal adenomas. Here, the crossing of ApcMin with cyclin D1-/- mice reduced the intestinal tumor number in animals genetically heterozygous or nullizygous for cyclin D1.

Trans-repression of beta-catenin activity by nuclear receptors.

The signaling/oncogenic activity of beta-catenin can be repressed by the activation of nuclear receptors such as the vitamin A, vitamin D, and androgen receptors. Although these receptors directly interact with beta-catenin and can sequester it away from its transcription factor partner T-cell factor, it is not known if this is the mechanism of trans-repression. Using several different promoter constructs and nuclear receptors and mammalian two-hybrid and mutation analyses we now show that interaction with the co-activator, p300, underlies the trans-repression of beta-catenin signaling by nuclear receptors and their ligands.

Beta-catenin binds to the activation function 2 region of the androgen receptor and modulates the effects of the N-terminal domain and TIF2 on ligand-dependent transcription.

Beta-catenin is a multifunctional molecule that is activated by signaling through WNT receptors. beta-Catenin can also enhance the transcriptional activity of some steroid hormone receptors such as the androgen receptor and retinoic acid receptor alpha. Androgens can affect nuclear translocation of beta-catenin and influence its subcellular distribution.

The role of cadherin, beta-catenin, and AP-1 in retinoid-regulated carcinoma cell differentiation and proliferation.

Vitamin A derivatives (retinoids) are potent regulators of cell proliferation and differentiation. Retinoids inhibit the function of the oncogenic AP-1 and beta-catenin/TCF pathways and also stabilize components of the adherens junction, a tumor suppressor complex. When treated with retinoic acid (RA), the breast cancer cell line, SKBR3, undergoes differentiation and reduction in cell proliferation.