ESTROGEN RECEPTOR ALPHA: IMPACT OF LIGANDS ON INTRACELLULAR SHUTTLING AND TURNOVER RATE IN BREAST CANCER CELLS.

   Estrogen receptors (alpha and beta) are members of the steroid/thyroid nuclear receptors superfamily of ligand-dependent transcription factors. Impact of the alpha isoform of estrogen receptor (ER) on breast cancer etiology and progression is now well established. Current therapeutic strategy to treat ER-positive breast cancer relies on the blockade of ER trancriptional activity by antiestrogens. Data accumulated during the last years on ER mechanism of action enable one to foresee new strategies. These data indeed reveal that ER is not statically bound to DNA at promoter sites of genes regulating cell proliferation and/or differentiation, but rather behaves as a very mobile protein continuously shuttling between targets located within various cellular compartments (i.e. membrane, microsomes, nucleus...). This allows the receptor to generate both non-genomic and genomic responses. Ligands, growth factors and 2^nd messengers produced downstream of activated membrane receptors modulate ER-mediated responses by interfering with the traffic patterns of the receptor, as well as by locally blocking its transient anchorage. Changes in ER turnover rate associated with these regulatory processes seem also to strongly influence the ability of the receptor to mediate gene transactivation. The present paper surveys these biological data and analyzes how they may be integrated into new drug design programs aimed at expanding our therapeutic armamentarium against breast cancer.


Summary

Introduction

Estrogen receptor ligands
Estrogens
Antiestrogens

Estrogen Receptor Alpha - Main Characteristics
ER Gene Structure and Expression
ER Chaperoning
ER Subcellular Distribution and Functions
Cell Nucleus
Plasma Membrane
Microsomes
Nucleocytoplasmic Translocation
ER Domains
ER-Mediated Transcription
Main Characteristics
Ligand-Induced Transcription
Ligand-Independent Transcription
Membrane ER-Associated Transcription
Implication of ER Proteosomal Degradation in ER Mediated Transcription
Ligand-Binding Domain: Structure and Conformation
G and A Binding Pockets
Key Aminoacids of the G Pocket Involved in Ligand Binding
Ligand-Induced Conformational Changes
Distribution and Molecular Heterogeneity

Regulation of ER Concentration in Breast Cancer
Importance of Assessing the Regulatory Mechanisms Governing ER Concentration
Regulation of ER mRNA Expression
Breast Cancer Cell Lines as Experimental Models for the Study of the Regulation of ER level
ER Turnover Rate
Influence of Ligands on ER Level
Influence of Protein Synthesis on Ligand-Induced ER Down Regulation
Influence of Ligands on Estradiol Binding Capacity

Therapeutic Agents Aimed at Modifying ER Shuttling and Turnover Rate in Breast Cancer Cells
Lack of Specificity of Most Compounds Under (pre)Clinical Investigation
ER Antagonists Preventing the Binding of Co-Regulators
Potential co-Repressor Mimics
Selective Enhancement of ER Degradation

Concluding Remarks

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Made in BELGIUM / WALLONIA / EUREGIO MAAS-RHINE - Fait en BELGIQUE / WALLONIE / EUREGIO MEUSE-RHIN - (Molecular breast cancer - Cancer du sein, aspects moléculaires) - Marc Lacroix & SciMedWeb® & InTextoResearch® 2006-2009