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

Abstract

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

Diverse Associations between ESR1 Polymorphism and Breast Cancer Development and Progression

“…3A). In these subjects, ERα is a promising therapeutic target and the use of the antiestrogen drug tamoxifen in targeted therapy can activate an invasion suppressor phenotype by restoring E-cadherin function (50)(51)(52). To this end, ERα may work in a ligand-independent manner, contributing to the therapeutic benefit in breast cancer patients carrying the haplotype composed of the wild-type (supposedly high expression) alleles of ESR1.…”

Expression of estrogen receptor β increases integrin α1 and integrin β1 levels and enhances adhesion of breast cancer cells

“…ERbÀ/À mice show reduced expression of the adhesion proteins, E-cadherin, occludin, connexin 32, and integrin a2 and an increase in proliferating cells in the lactating stage of the mammary gland (Forster et al, 2002). Furthermore, knockdown of ERb in HC11 mouse mammary epithelial cells is associated with increased proliferation, loss of contact growth inhibition ) and E-cadherin downregulation (Helguero et al, 2008). Overall, these findings indicate that there is a role for ERb in the regulation of cell adhesion and point out ERb as a modulator of invasion and proliferation.…”

DN‐R175H p53 mutation is more effective than p53 interference in inducing epithelial disorganization and activation of proliferation signals in human carcinoma cells: Role of E‐cadherin

“…36 Distinction between surface and intracellular E-cadherin is important since post-transcriptional processes involving its endocytosis, endosomal sorting and lysosomal-mediated degradation play a major role in dynamically modulating cell surface Ecadherin levels. 37 Moreover, in normal enterocytes undergoing anoikis, loss of surface E-cadherin precedes its subsequent intracellular disappearance and cell death. 38 In contrast, the dramatic loss of surface and intracellular E-cadherin induced by the DNmutant p53 R175H (Figs.…”