Mutations and deletions that result in the stabilization of beta-catenin are frequently found in a number of tumors, including those of the colon, the liver and the ovary, but are less frequently found in breast cancer.
Breast cancer-specific mutations in CK1epsilon inhibit Wnt/beta-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration.
Wnt signaling is associated with initiation and progression process in many tumor types, and alterations in β-Catenin explain only a small proportion of aberrant signaling found in breast cancer, indicating that other Wnt signaling components and/or regulators as GSK3β may be involved.
Whereas some oncogenic pathways have high correlations to breast cancer subtype (RAS, CTNNB1, p53, HER1), others have high variability of activity within a specific subtype (MYC, E2F3, SRC), reflecting biology independent of common clinical factors.
For this reason, in present study, the alterations (deletion/methylation/mutation/expression) of MCC and CTNNBIP1 were analyzed in BC of Indian patients (N=120) followed by expression/mutation analysis of β-catenin.
Nuclear localization of β-catenin showed significant association with alterations in the antagonists and was also significantly high in the ER-/PR- BC samples.
Here, we report a comprehensive study of the contribution of genetic variation in six genes encoding the beta-catenin destruction complex (APC, AXIN1, AXIN2, CSNK1D, CSNK1E, and GSK3B) to breast cancer using a Mayo Clinic Breast Cancer Case-Control Study.
Our results suggest that genetic defects in beta-catenin is not common in invasive ductal breast cancers, whereas mutations in other components of the Wnt signaling pathway should be considered.
Hypermethylation of the APC promoter CpG island was detected in 18 of 50 (36%) primary breast cancers and in none of 21 non-cancerous breast tissue samples, although no mutations of the APC and beta- catenin were found.
In conclusion, rAd.DCN inhibits tumor growth and lung metastasis of breast cancer via regulating wnt/β-catenin, vascular endothelial growth factor (VEGF), and Met pathways, and modulating the antitumor inflammatory and immune responses.Considering that i.v. delivery was much more effective in preventing lung metastasis, systemic delivery of rAd.DCN might be a promising strategy to treat breast cancer lung metastasis.
An analysis of breast cancer patients led us to identify c-Myb as an activator of Wnt/β-catenin signaling. c-Myb interacted with the intracellular Wnt effector β-catenin and coactivated the Wnt/β-catenin target genes Cyclin D1 and Axin2 Moreover, c-Myb controlled metastasis in an Axin2-dependent manner.
On the other hand, in sporadic tumor tissues, the level of Wnt5a mRNA was significantly lower compared to normal tissues (p=0.031) and lower still in those showing more aggressive behavior, suggesting that Wnt5a, a ligand involved in the noncanonical Wnt/β-catenin pathway, could act as a tumor suppressor gene in breast cancer.
Collectively, these data indicate that Wnt/beta-catenin activation is an important feature of basal-like breast cancers and is predictive of worse overall survival, suggesting that it may be an attractive pharmacological target for this aggressive breast cancer subtype.
Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. beta-catenin is a critical coactivator in this signaling pathway and is regulated in a complex fashion by phosphorylation, degradation, and nuclear translocation.
The Wnt/β-catenin signaling pathway regulates various processes that are important for cancer progression, and emerging evidences have shown a close interaction between Wnt/β-catenin and ERα signaling. miR-190 is also involved in ER signaling and our previous study indicated that miR-190 suppresses breast cancer metastasis.
Our results show that the antitumor effect of DADS on TNBC cells is mediated by the β-catenin pathway, suggesting that DADS could be used as a potential therapeutic agent for treating or preventing breast cancer.
Several important transcription factors involved in this disease, such as PTEN, p53 and beta-catenin, have been identified and researched in-depth as candidates for targeted therapy in breast cancer.
These findings indicate MNK-eIF4E-β-catenin is an activator of the breast cancer cell response to chemotherapy and highlights the therapeutic value of inhibiting MNK to overcome chemoresistance in breast cancer.