Estrogen Receptor Mutations in Human Disease

Abstract

As early as the 1800s, the actions of estrogen have been implicated in the development and progression of breast cancer.The estrogen receptor (ER) was identified in the late 1950s and purified a few years later.However, it was not until the 1980s that the first ER was molecularly cloned, and in the mid 1990s, a second ER was cloned.These two related receptors are now called ER␣ and ER␤, respectively.Since their discovery, much research has focused on identifying alterations within the coding sequence of these receptors in clinical samples.As a result, a large number of naturally occurring splice variants of both ER␣ and ER␤ have been identified in normal epithelium and diseased or cancerous tissues.In contrast, only a few point mutations have been identified in human patient samples from a variety of disease states, including breast cancer, endometrial cancer, and psychiatric diseases.To elucidate the mechanism of action for these variant isoforms or mutant receptors, experimental mutagenesis has been used to analyze the function of distinct amino acid residues in the ERs.This review will focus on ER␣ and ER␤ alterations in breast cancer.(Endocrine Reviews 25: 869 -898, 2004) I. Introduction II.ER Structure III.Roles of ER␣ and ER␤ IV.ERs in Human Breast Cancer V. Splicing and Genetic Alterations of ER␣ A. Alternative exons in the 5ЈUTR B. mRNA splice variants C. ER␣ experimental splice variants D. mRNA splice variants summary E. Natural mutations of ER␣ identified in human tissue samples F. Natural mutations conclusions G. Experimental mutations H. ER␣ experimental mutations summary VI.Splicing and Genetic Alterations of ER␤ A. Alternative exons in the 5ЈUTR B. Natural mRNA splice variants C. mRNA splice variants summary D. Natural point mutations identified in human tissue samples E. Experimental point mutations F. ER␤ summary VII.