Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Apr 10, 2016; 7(2): 160-173
Published online Apr 10, 2016. doi: 10.5306/wjco.v7.i2.160
Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate
Frederik Holst
Frederik Holst, Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, Boston, MA 02215, United States
Frederik Holst, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
Author contributions: Holst F wrote this review.
Conflict-of-interest statement: Holst F has royalty interest associated with intellectual property of ZytoVision GmbH concerning patent US8101352B2 “Detection of ESR1 Amplification in Breast Cancer” and according EU patent application in the European Union.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Frederik Holst, PhD, Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, 450 Brookline Avenue, Boston, MA 02215, United States.
Telephone: +1-617-6324515
Received: July 2, 2015
Peer-review started: July 7, 2015
First decision: September 18, 2015
Revised: January 5, 2016
Accepted: February 14, 2016
Article in press: February 16, 2016
Published online: April 10, 2016

Twenty-five years ago, Nembrot and colleagues reported amplification of the estrogen receptor alpha gene (ESR1) in breast cancer, initiating a broad and still ongoing scientific debate on the prevalence and clinical significance of this genetic aberration, which affects one of the most important genes in breast cancer. Since then, a multitude of studies on this topic has been published, covering a wide range of divergent results and arguments. The reported prevalence of this alteration in breast cancer ranges from 0% to 75%, suggesting that ESR1 copy number analysis is hampered by technical and interpreter issues. To date, two major issues related to ESR1 amplification remain to be conclusively addressed: (1) The extent to which abundant amounts of messenger RNA can mimic amplification in standard fluorescence in situ hybridization assays in the analysis of strongly expressed genes like ESR1, and (2) the clinical relevance of ESR1 amplification: Such relevance is strongly disputed, with data showing predictive value for response as well as for resistance of the cancer to anti-estrogen therapies, or for subsequent development of cancers in the case of precursor lesions that display amplification of ESR1. This review provides a comprehensive summary of the various views on ESR1 amplification, and highlights explanations for the contradictions and conflicting data that could inform future ESR1 research.

Keywords: Estrogen receptor alpha gene, Breast cancer, Tamoxifen, Gene amplification, Methodology

Core tip: The estrogen receptor alpha gene gene (ESR1) is one of the most important genes in breast cancer, but the prevalence of ESR1 amplification is matter of ongoing debate. A number of studies suggest that technical issues and lack of standards contribute to the discrepant findings. Future studies should focus on the potential clinical relevance of this phenomenon.