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.

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

“…Recognition of the importance of APC and β-catenin mutations in colon cancer has provided strong evidence that the pathway plays a major role in the genesis of at least one major type of human cancer (30,31). Although not as frequently mutated in other tumor types, increased Wnt pathway activation and epigenetic silencing of Wnt antagonists has been noted in several tumor types (7,(32)(33)(34)(35)(36)(37).…”

Epigenetics in cancer: Targeting chromatin modifications

“…There is a strong causative link between the silencing of genes involved in DNA repair (i.e., hMLH1, BRCA1) and cell transformation (17). In addition to negative effects on DNA repair, pathways such as the Wnt/β-catenin pathway that regulate cell proliferation and epithelial-to-mesenchymal transition (EMT) can be epigenetically controlled (18). Epigenetic silencing of genes including APC, Wnt inhibitory factor-1 (WIF-1), and frizzled-related proteins (SFRP) occurs in numerous cancer types, which often results in increased activity of β-catenin transcriptional activity (18,19).…”

“…In addition to negative effects on DNA repair, pathways such as the Wnt/β-catenin pathway that regulate cell proliferation and epithelial-to-mesenchymal transition (EMT) can be epigenetically controlled (18). Epigenetic silencing of genes including APC, Wnt inhibitory factor-1 (WIF-1), and frizzled-related proteins (SFRP) occurs in numerous cancer types, which often results in increased activity of β-catenin transcriptional activity (18,19). There is clearly growing awareness of the importance of epigenetic deregulation in early cancer predisposition and development as evidenced by the growing list of genes with tumor suppressor activity that are often epigenetically silenced but rarely genetically mutated in the pre-invasive stages of many cancers (1).…”

AXIN2 Polymorphisms, the β-Catenin Destruction Complex Expression Profile and Breast Cancer Susceptibility

“…Gene expression and epigenetic changes are part of signaling pathways, like Wnt pathway, have been considered in the etiology of breast cancer (Klarmann et al, 2008).…”