The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression

Malignant breast cancer is a disease arising in the ductal and lobular epithelium of the mammary gland. Intercellular interactions are critical for the dynamic differentiation processes activated periodically throughout life in normal breast epithelium, as well as for the induction and maintenance of differentiated tissues in adults. In the past few years there has been increasing interest in E-cadherin-mediated cell–cell adhesion and cell–extracellular matrix adhesion as prime mediators of epithelial differentiation.E-cadherin is a glycoprotein with a large extracellular domain comprising five cadherin-motif subdomains, a single-pass transmembrane segment and a short conserved cytoplasmic domain, which interacts with several proteins collectively termed catenins. Several of these catenins belong to the Armadillo protein family, whereas α-catenins are vinculin-related molecules. The central armadillo domain of either β-catenin or plakoglobin (γ-catenin) interacts directly with a carboxy-terminal cytoplasmic domain of the E-cadherin protein. The same armadillo molecules also interact with α-catenin, and the latter is directly and indirectly linked to filamentous actin. Another armadillo catenin, p120ctn, interacts with a more membrane-proximal cytoplasmic domain of cadherins. The 120ctn protein is involved in strengthening cadherin-containing adhesion junctions [1]. Whereas β-catenin is a proto-oncogene by virtue of its important role in the Wnt signaling pathway [2], E-cadherin exerts a potent invasion-suppressing role in tumor cell lines and in vivo tumor model systems [3,4,5,6]. Forced expression of E-cadherin decreased proliferation of different mammary carcinoma cell lines [4,7]. Precancerous hyperproliferation and sustained activation of the Ras-MAPK cascade was recently found in skin with tissue-specific ablation of α-catenin [8].Breast E-cadherin is expressed in normal adults in luminal epithelial cells, whereas expression of P-cadherin is confined to myoepit