Different Roles of Estrogen Receptors α and β in the Regulation of E-Cadherin Protein Levels in a Mouse Mammary Epithelial Cell Line

Two estrogen receptors (ER alpha and ER beta) are found throughout the mammary gland. Evidence indicates that, while ER alpha transduces proliferation signals, ER opposes this effect and is necessary for epithelial differentiation. Using mouse mammary epithelial cells, we have previously shown that activation of ER beta opposes ER alpha-induced proliferation and increases apoptosis. Furthermore, stable knockdown of ER beta resulted in loss of growth contact inhibition. In this work, we report that loss of ER beta is associated with a decrease of E-cadherin protein levels through different posttranscriptional regulatory mechanisms. Ligand activation of ER alpha induced E-cadherin extracellular shedding and internalization only in the absence of ER beta, followed by lysosomal degradation. Loss of ER also led to an increase of E-cadherin uptake in a ligand-independent manner through mechanisms that required caveolae formation. Proteasome activity was necessary for both mechanisms to operate. Increased E-cadherin internalization correlated with the up-regulation of beta-catenin transcriptional activity and impaired morphogenesis on Engelbreth-Holm-Swarm matrix. Taken together, these results emphasize the role of epithelial ER,3 in maintaining cell adhesion and a differentiated highlight the potential importance of ER phenotype and highlight design of specific agonists for use in breast cancer therapy. [Cancer Res 2008;68(21):8695-704]