P-Cadherin Is Up-Regulated by the Antiestrogen ICI 182,780 and Promotes Invasion of Human Breast Cancer Cells

Joana Paredes,Fernanda Milanezi,Fernando Schmitt,Veronique Stove,Veerle Van Marck,Lara Derycke,Christophe Stove,Marc Bracke,Marc Mareel

doi:10.1158/0008-5472.can-04-0795

Joana Paredes, Fernanda Milanezi + Show 7 more

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https://doi.org/10.1158/0008-5472.can-04-0795

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Abstract

P-cadherin expression in breast carcinomas has been associated with tumors of high histologic grade and lacking estrogen receptor-alpha, suggesting a link between these proteins. In the MCF-7/AZ breast cancer cell line, blocking estrogen receptor-alpha signaling with the antiestrogen ICI 182,780 induced an increase of P-cadherin, which coincided with induction of in vitro invasion. Retroviral transduction of MCF-7/AZ cells, as well as HEK 293T cells, showed the proinvasive activity of P-cadherin, which requires the juxtamembrane domain of its cytoplasmic tail. This study establishes a direct link between P-cadherin expression and the lack of estrogen receptor-alpha signaling in breast cancer cells and suggests a role for P-cadherin in invasion, through its interaction with proteins bound to the juxtamembrane domain.

Highlights

Classical cadherins are a superfamily of transmembrane glycoproteins responsible for calcium-dependent cell– cell adhesion, mediating homophilic protein interactions [1]
These are modulated by their conserved cytoplasmic juxtamembrane domain and catenin-binding domain, linking them to the actin cytoskeleton. ␤, ␥, p120, and ␣-Catenins are the best-documented interaction partners [2]. ␤-Catenin is a signaling molecule, implicated in tissue patterning, of which the functions are regulated by binding to the catenin-binding domain of cadherins and by interactions with receptor tyrosine kinases and transcription factors of the lymphocyte enhancer factor/T-cell factor family [2]
P120-catenin was identified as a substrate for Src and several receptor tyrosine kinases and interacts directly with the juxtamembrane domain of cadherins, modulating cadherin clustering and cell motility in a cell-type and phosphorylation state-dependent way [3]

Summary

Introduction

Classical cadherins are a superfamily of transmembrane glycoproteins responsible for calcium-dependent cell– cell adhesion, mediating homophilic protein interactions [1]. These are modulated by their conserved cytoplasmic juxtamembrane domain and catenin-binding domain, linking them to the actin cytoskeleton. ␤-Catenin (and perhaps ␥-catenin) is a signaling molecule, implicated in tissue patterning, of which the functions are regulated by binding to the catenin-binding domain of cadherins and by interactions with receptor tyrosine kinases and transcription factors of the lymphocyte enhancer factor/T-cell factor family [2]. P120-catenin was identified as a substrate for Src and several receptor tyrosine kinases and interacts directly with the juxtamembrane domain of cadherins, modulating cadherin clustering and cell motility in a cell-type and phosphorylation state-dependent way [3]. The invasion suppressor function of normally expressed E-cadherin may be overcome by the aberrant expression of N-cadherin [5] or cadherin-11 [6], which have been associated with progression of breast carcinoma through interference with E-cadherin function [7]

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