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

Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

Requests for reprints: Luisa A. Helguero, Unit for Nuclear Receptor Biology, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Hälsovägen 7, 141 57 Stockholm, Sweden. Phone: 46-8-608-9277; Fax: 46-8-774-5538; E-mail: luisa.helguero{at}ki.se.

Key Words: E-cadherin • estrogen receptors • internalization • degradation • mammary epithelial cells

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

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