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      ESR1 mutations: Pièce de résistance

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          Abstract

          Estrogen and estrogen receptor-alpha (ER) signaling are important factors in the pathogenesis and treatment of ER-positive breast cancers. Therefore targeted therapies against ER, known as endocrine therapies, are widely used in the treatment of ER-positive breast cancers. While these therapies have shown great success, de novo and acquired resistance are common. The approach to the problem of endocrine therapy resistance is two-fold: identify the mechanisms of resistance and develop alternative treatments to overcome these mechanisms. This review focuses on the progress and integration of these two aspects of resolving endocrine therapy resistance in ER-positive breast cancer patients.

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          Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts.

          Shunqiang Li, Dong Shen, Jieya Shao … (2013)
          To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
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            D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer.

            Keren Merenbakh-Lamin, Noa Ben-Baruch, Adva Yeheskel … (2013)
            Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor α (ERα)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERα expression, altered activity of coregulators, and cross-talk between the ERα and growth factor signaling pathways. To our knowledge, acquired mutations of the ERα have not been described as mediating endocrine resistance. Samples of 13 patients with metastatic breast cancer were analyzed for mutations in cancer-related genes. In five patients who developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment. Structural modeling indicated that D538G substitution leads to a conformational change in the ligand-binding domain, which mimics the conformation of activated ligand-bound receptor and alters binding of tamoxifen. Indeed, experiments in breast cancer cells indicated constitutive, ligand-independent transcriptional activity of the D538G receptor, and overexpression of it enhanced proliferation and conferred resistance to tamoxifen. These data indicate a novel mechanism of acquired endocrine resistance in breast cancer. Further studies are needed to assess the frequency of D538G-ERα among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity.
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              Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer.

              Frederik Holst, Phillip Stahl, Christian Ruiz … (2007)
              Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, we detected a single-gene amplification of the ESR1 gene, which encodes estrogen receptor alpha, at 6q25. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein overexpression, compared with 66.6% cancers without ESR1 amplification (P < 0.0001). In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor-expressing cancers without ESR1 amplification (P = 0.023). Notably, we also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers.
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                Author and article information

                Contributors
                Berry Button
                Ben Ho Park
                Journal
                Journal ID (nlm-ta): Genes Dis
                Journal ID (iso-abbrev): Genes Dis
                Title: Genes & Diseases
                Publisher: Chongqing Medical University
                ISSN (Print): 2352-4820
                ISSN (Electronic): 2352-3042
                Publication date PMC-release: 19 April 2016
                Publication date Collection: June 2016
                Publication date (Electronic): 19 April 2016
                Volume: 3
                Issue: 2
                Pages: 124-129
                Affiliations
                [a ]The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
                [b ]Department of Chemical and Biomolecular Engineering, The Whiting School of Engineering, The Johns Hopkins University, Baltimore, MD, United States
                Author notes
                [∗ ]Corresponding author. bpark2@ 123456jhmi.edu
                [c]

                1650 Orleans Street, CRBI, Room 116, Baltimore, MD 21287, United States.

                [d]

                1650 Orleans Street, CRBI, Room 151, Baltimore, MD 21287, United States.

                Article
                Publisher ID: S2352-3042(16)30011-3
                DOI: 10.1016/j.gendis.2016.03.005
                PMC ID: 6150098
                SO-VID: 878cfafb-d096-4d65-b751-ad81afafabbf
                Copyright © Copyright © 2016, Chongqing Medical University. Production and hosting by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 7 February 2016
                Date accepted : 29 March 2016
                Categories
                Subject: Article

                Keywords: breast cancer,circulating tumor dna,esr1,estrogen receptor,mutation,plasma
                Data availability:
                Keywords: breast cancer, circulating tumor dna, esr1, estrogen receptor, mutation, plasma

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