The prevalence of APC truncation mutants in colorectal tumors and the ability of these alleles to act dominantly to inhibit the mitotic spindle place chromosome instability at the earliest stage of colorectal cancer progression (i.e., prior to deregulation of beta-catenin).
Our results indicate that somatic beta-catenin activating mutations contribute only to a minor part of human colorectal tumors and that germline beta-catenin mutations do not play a role in the variability of symptoms in FAP.
Alterations of phosphorylation sites within the CTNNB1 gene, which codes for beta-catenin has been reported to occur in about one-half of colorectal tumors without APC-gene mutations.
Aberrant activation of this signaling pathway is a key early event in the development of colorectal neoplasms, and is mainly caused by loss of function mutations in Adenomatous Polyposis Coli (APC), and less frequently by β-catenin stabilization mutations via missense or interstitial genomic deletions in CTNNB1.
We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin).
Some colorectal tumors with wild-type adenomatous polyposis coli gene have activating mutations in beta-catenin (encoded by CTNNB1) that result in decreased phosphorylation by GSK-3beta and increased signaling through the Tcf/Lef transcription factors.
Aberrant activation of Wnt signaling caused by mutations in the tumor suppressor adenomatous polyposis coli or beta-catenin is a critical event in the development of human colorectal tumors.
Therefore, beta-catenin might have an impact on the capacity of colorectal tumors for invasion and metastasis, as well as dormancy, which are hallmarks of cancer.
OVOL2 is a colorectal tumor suppressor that blocks WNT signaling by facilitating the recruitment of histone deacetylase 1 to the TCF4-β-catenin complex.
These results support (i) that vitamin D, alone or in combination with calcium, may modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms; (ii) vitamin D as a potential chemopreventive agent against colorectal neoplasms; and (iii) the potential of APC, β-catenin, and E-cadherin expression as treatable, pre-neoplastic risk biomarkers for colorectal neoplasms.
The level of Dickkopf-4 was positively correlated with fibroblast growth factor-20 (r(s) = 0.61, P = 0.00017), a representative beta-catenin transcriptional target gene, and with the degree of nuclear accumulation of beta-catenin in colorectal tumors.
Because beta-catenin is constitutively active in the majority of colorectal tumors, it is unlikely that sFRP1 can act in the canonical Wnt response pathway.
A majority of human colorectal tumors and hepatomas are known to possess a constitutively active canonical Wnt/beta-catenin/TCF signaling pathway, also express CR-1.
Thus, by far the most common mutations in colorectal tumors, found in the Wnt-signaling pathway and leading to the stabilizing of beta-catenin, might influence invasion by altering adhesive properties and EMT of tumor cells.
Aberrant activation of Wnt signaling caused by mutations in adenomatous polyposis coli (APC) or beta-catenin is a critical event in the development of human colorectal tumors.
Thus, through protein-protein interaction, EDD stabilizes APC and up-regulates APC's function to inhibit beta-catenin, suggesting that EDD could act as a colorectal tumor suppressor.
Mutations in APC and beta-catenin, despite occurring in the same genetic pathway, show differing biological properties, a phenomenon that has previously been demonstrated in colorectal neoplasms.