Basal-like breast tumors are largely overlapping with the triple-negative subtype defined by the absence of Estrogen Receptor and Progesterone Receptor expression, and Her2 overexpression, and tend to be locally invasive and recur at high frequency (Meyers et al 2011, Pazaiti and Fentiman 2011). Results from animal models and the study of human cancers suggest that E-Cadherin functions as a tumor suppressor and an invasion suppressor (Cowin et al 2005). E-Cadherin is often absent or nonfunctional in invasive breast cancers and this is commonly attributed to epigenetic silencing of the E-Cadherin gene, Cdh1 (Jeanes et al 2008). Therefore, efforts have been directed toward reactivating E-Cadherin expression in cancers (Ou et al 2007, Papageorgis et al 2010). However, data also indicate that E-Cadherin is expressed in some invasive breast cancers where it is mislocalized to cytoplasmic vesicles (Corsino et al 2008, Facina et al 2010). Thus, reinstating E-Cadherin expression may not restore its tumor and invasion suppressive actions unless the posttranslational mechanisms that nullify E-Cadherin function in cancers are also blocked.
E-Cadherin is a homophilic cell-cell adhesion molecule whose extracellular domain binds to the extracellular domain of E-Cadherin on adjacent cells and whose cytoplasmic domain binds a number of proteins including p120ctn, β-Catenin, and γ-Catenin, also referred to as Junctional Plakoglobin. The latter two proteins bind α-Catenin, which is thought to either directly or indirectly couple the E-Cadherin complex with the Actin cytoskeleton. These multiprotein E-Cadherin-containing complexes play a critical physical role in mediating the formation of adherens junctions in epithelial tissues (Baum and Georgiou 2011), and serve to control the activity of several complex components that also function as transcriptional regulators (Daniel 2007, Heuberger and Birchmeier 2010). As such, mechanisms that converge on E-Cadherin provide an opportunity to address unmet needs in treatment and prevention of disease.