Abstract
Two estrogen receptors (ERalpha and ERbeta) are found throughout the mammary gland. Evidence indicates that, while ERalpha transduces proliferation signals, ERbeta opposes this effect and is necessary for epithelial differentiation. Using mouse mammary epithelial cells, we have previously shown that activation of ERbeta opposes ERalpha-induced proliferation and increases apoptosis. Furthermore, stable knockdown of ERbeta resulted in loss of growth contact inhibition. In this work, we report that loss of ERbeta is associated with a decrease of E-cadherin protein levels through different posttranscriptional regulatory mechanisms. Ligand activation of ERalpha induced E-cadherin extracellular shedding and internalization only in the absence of ERbeta, followed by lysosomal degradation. Loss of ERbeta 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 ERbeta in maintaining cell adhesion and a differentiated phenotype and highlight the potential importance of ERbeta for the design of specific agonists for use in breast cancer therapy.
Highlights
Estrogen receptors (ER) exist as two isoforms, ERa and ERh, with similar affinity for the endogenous estrogen 17h-estradiol (E2) but considerable selectivity for other natural and synthetic compounds [1,2,3]
In HC11 wild-type (HC11-wt), ctrol-siRNA, and siERa cells, E-cadherin was up-regulated by E2, whereas no effect was observed with PPT
In siERh cells, E-cadherin was down-regulated by both E2 and PPT and E2-induced down-regulation was reversed by the antiestrogen ICI 182 780 (Fig. 1A)
Summary
Estrogen receptors (ER) exist as two isoforms, ERa and ERh, with similar affinity for the endogenous estrogen 17h-estradiol (E2) but considerable selectivity for other natural and synthetic compounds [1,2,3]. Estrogens are important for mammary gland morphogenesis and differentiation. They were thought to act through paracrine mechanisms, requiring stromal ERa and growth factor signaling [6,7,8]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Doi:10.1158/0008-5472.CAN-08-0788 gland, the epithelial compartment is necessary and sufficient to transduce estrogen signaling through a paracrine mechanism [9]. ERh is widespread throughout the mammary tissue, and studies in ERhÀ/À mice have revealed its role in regulating cell adhesion proteins [10,11,12], such as E-cadherin, occludin, and connexin 32, in the lactating mammary gland [10]. The mechanisms behind this regulation remain to be elucidated
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