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About the Authors:
Rajendra G. Mehta
* E-mail: [email protected]
Affiliation: IIT Research Institute, Chicago, Illinois, United States of America
Michael Hawthorne
Affiliation: IIT Research Institute, Chicago, Illinois, United States of America
Rajeshwari R. Mehta
Affiliation: IIT Research Institute, Chicago, Illinois, United States of America
Karen E. O. Torres
Affiliation: GenUs Biosystems, Northbrook, Illinois, United States of America
Xinjian Peng
Affiliation: IIT Research Institute, Chicago, Illinois, United States of America
David L. McCormick
Affiliation: IIT Research Institute, Chicago, Illinois, United States of America
Levy Kopelovich
Affiliation: Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, United States of America
Introduction
Estrogen action in target tissues is mediated by binding to specific nuclear receptors, estrogen receptors α and β (ERα and ERβ) [1]. ERα and ERβ are ligand-regulated transcription factors, and each has several isoforms; these receptors play key roles in the regulation of cell proliferation and differentiation in the breast, uterus, and other tissues [2]. Following estrogen binding, ERs bind to estrogen response elements (EREs) in the promoter regions of estrogen-responsive genes [3], resulting in a cascade of downstream responses.
Although murine ERα and ERβ demonstrate 97% sequence homology at the DNA binding domain [4], the two receptors are clearly distinct. The genes for ERα and ERβ are located on different chromosomes [5]; the two receptors demonstrate different distribution patterns in estrogen target tissues; and the receptors appear to regulate transcription via different mechanisms. ERα and ERβ also have different ligand binding affinities and respond independently to ligand binding [6]. Most importantly, activation of ERα results in substantially different effects in estrogen target tissues than does activation of ERβ).
The contrasting effects of ERα activation and ERβ activation appear to be both organ-specific and context-dependent [6]. In the normal breast, ERβ is more abundant than is ERα; recent data suggest that high levels of ERβ can down-regulate the expression of ERα [7]. Activation of ERα supports cell proliferation in the breast and other tissues [8]; ERα content has been proposed as a marker to distinguish hormone-dependent breast cancers from hormone-independent breast cancers [5]. By contrast, activation of ERβ is antiproliferative in the breast and other tissues [9]. Because ERα and ERβ demonstrate both qualitative and quantitative differences in activity, understanding their distinct roles in normal and...