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Cell Rep. 2018 Aug 7;24(6):1434-1444.e7. doi: 10.1016/j.celrep.2018.07.009.

Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.

Author information

1
Department of Medicine, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
2
Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
3
Cancer Biology Division, Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO 63110, USA; Institute for Informatics (I(2)), Washington University in St. Louis, St. Louis, MO 63110, USA.
4
Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
5
Department of Medicine, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
8
Department of Breast and Endocrine Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0375, Japan.
9
First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
10
Department of Obstetrics and Gynecology, University of São Paulo School of Medicine (FMUSP), Cerqueira César, São Paulo 01246-903, Brazil.
11
Department of Obstetrics and Gynecology, Faculty of Medical Science, State University of Campinas - UNICAMP, Campinas, São Paulo 13083-970, Brazil.
12
Queens' College, University of Cambridge, Cambridge CB3 9ET, UK.
13
Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
14
Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
15
University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
16
School of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
17
Alliance Statistical Center, Mayo Clinic, Rochester, MN 55905, USA.
18
Department of Breast Surgical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
19
Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
20
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USA.
21
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
22
Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; The McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.
23
Department of Medicine, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: mjellis@bcm.edu.

Abstract

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.

KEYWORDS:

EMT; ESR1 fusions; PDX; breast cancer; endocrine therapy resistance; metastasis

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