Alterations and correlations of the components in the Wnt signaling pathway and its target genes in breast cancer

Abstract

Both cyclin D1 and c-myc are key molecules in breast cancer carcinogenesis, and their transcriptional level and stability are regulated through several signaling pathways, including the Wnt signaling pathway. We performed immunohistochemical and mutational analyses of Wnt signaling components to investigate the association of Wnt signaling alterations with breast cancer carcinogenesis using 49 surgically resected primary breast cancer samples. Positive staining of cyclin D1 and c-myc was observed in 55.1% and 30.6% of the 49 breast cancer samples, respectively. Aberrant cytoplasmic expression of β-catenin, which indicates the existence of alterations in the Wnt signaling pathway, was observed in 38.8% of breast cancer samples, though no mutation was found in the β-catenin and Axin 1 genes. Reduced expression of APC was observed in 34.7% of samples. Statistical analysis revealed strong correlations between overexpression of βcatenin and that of cyclin D1 and c-myc (p=0.0001 and 0.0117, respectively). Furthermore, overexpression of β-catenin was significantly correlated with reduced expression of APC (p=0.0127). Wnt signaling alterations were frequently observed in breast cancer from the results of β-catenin immunohistochemistry, although no mutation in the components of the Wnt signaling pathway was found in the present study. Based on the statistical analyses, we speculated that reduced expression of APC leads to overexpression of β-catenin, and aberrant expression of cyclin D1 and cmyc mainly depends on alterations in the Wnt signaling pathway in breast cancer.

Evaluation of a variant in the transcription factor 7‐like 2 (TCF7L2) gene and prostate cancer risk in a population‐based study

“…This in turn leads to a series of molecular events involving β-catenin, axin, adenomaous polyposis coli (APC), and glycogen synthase kinase 3β (GSK-3β), that in the absence of Wnt stimulation target β-catenin for degradation. Aberrant activation of this pathway due to mutations in key components, such as the APC or β-catenin genes, has been described in colorectal (16,17), breast (18), head, neck (19), and oral (20) cancers, as well as in melanoma (21). Similar mutations have also been detected in a subset of prostate cancers (22)(23)(24).…”

Cytoplasmic Localization of β-Catenin is a Marker of Poor Outcome in Breast Cancer Patients

“…The molecular mechanisms that allow the transfer of membrane bound to cytoplasmic localization is largely unknown, but could be due to changes in adenomatous polyposis coli (APC) or axin, which maintains high β-catenin levels in the cytoplasm (29), APC shuttling (30), or galectin-3 recruiting β-catenin from cell adhesion to signaling pathways (31). Low APC expression is associated with β-catenin overexpression and localization in the cytoplasm in breast cancer cells (32). In breast cancer, APC (33) and Axin1 mutations are rare (32), but other events, such as methylation, as described in the APC promoter of invasive breast cancer patients (34), could regulate APC levels and thus β-catenin accumulation.…”

Notch, Myc and Breast Cancer

“…82 It is also notable that in breast cancers the expression level of Myc, which is a known direct transcriptional target of the Wnt/Tcf pathway, 83 has been strongly correlated with Wnt signaling components. 84 …”