Molecular mechanisms controlling E-cadherin expression in breast cancer

Abstract

Disruption of cell-cell adhesion, which is essential for the maintenance of epithelial plasticity and is mediated by a class of proteins called cadherins, is an initial event in the progression of cancer. Cadherins are Ca(2+)-dependent transmembrane proteins that are associated with actin via other cytoplasmic proteins. Disruption of cell-cell adhesion during cancer progression is an important event during cancer initiation and metastasis. E-cadherin, one of the most widely studied tumor suppressors in breast cancer, belongs to a family of calcium-dependent cell adhesion molecules. Various signaling molecules and transcription factors regulate the expression of E-cadherin. Loss of E-cadherin has been reported to induce epithelial-mesenchymal transition in several cancers. This review highlights recent advances in defining the mechanisms that regulate E-cadherin expression in breast cancer.

Figure 1. Schematic representation of different domains of E-cadherin

E-cadherin is transmembrane glycoprotein with four extracellular domains (EC domain) with several Ca²⁺ binding and adhesive recognition site, one membrane proximal extracellular domain (MPED), transmembrane domain and cytoplasmic domain. Human E-cadherin is synthesized as pro-peptide of 1036 amino acids. Functional human E-cadherin is 882 amino acids protein with first 154 amino acids are involved in signaling and processing to the membrane.

Figure 2. Schematic illustration of E-cadherin in adherens junction formation

E-cadherin forms homodimer in the extracellular domain in a Ca²⁺ dependent manner, while cytoplasmic domain binds with catenin and in turn regulates actin reorganization.

Figure 3. Role of various signaling pathways in modulating the expression of E-cadherin

Different E-cadherin signaling pathways regulates the key process of epithelial mesenchymal transition and the progression of breast cancer

Figure 4. Zinc finger transcription factors target the proximal region of E-cadherin promoter in regulating its expression

Zinc finger transcription factors are over expressed in metastatic breast cancer cells, and they regulate the expression of E-cadherin through binding with the E-box of the E-cadherin promoter.