Epigenetic gene silencing in the Wnt pathway in breast cancer

Abstract

Breast cancer is one of the most common malignancies in women. Despite advances in treatment of endocrine-dependent tumors, the complete molecular basis of transformation is still unknown. What is clear is that a variety of genetic lesions and epigenetic modifications are present in the neoplasm. Disregulation of several signaling pathways is known to be associated with breast cancer development, among them is the wingless and integration site growth factor (Wnt) pathway. While genetic mutations of certain components of this pathway, such as APC, are significant contributing factors for colorectal cancers, they are typically not the predominate mechanism associated with breast cancer. Instead, it appears that DNA hypermethylation leads to aberrant regulation of the Wnt pathway in breast cancer, and as such, this review focuses on the epigenetic regulation of Wnt pathway components in breast cancer.

Figure 1.

Simplified cartoon of the Wnt signaling pathway. (A) In the absence of Wnt or if Wnt cannot bind Frizzled (FRZ) receptor due to sequestration by Wnt inhibitory factor (WIF-1) or frizzled-related protein (SFRP), β-catenin is phosphorylated and degraded, and control over differentiation and proliferated is maintained by the cell. (B) Wnt binding to FRZ and low-density lipoprotein receptor-related protein (LRP) clusters assembled on a Dishevelled (Dvl) scaffold allows β-catenin to accumulate in the cytoplasm and then translocate to the nucleus where, in complex with transcription factors TCF/LEF-1, various genes for proliferation and epithelial-to-mesenchymal transition (EMT) are activated.