Abstract
SUMMARYRNA 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.
Highlights
The etiology of endocrine therapy resistance in estrogen receptor-positive (ER+) breast cancer is complex (Ma et al, 2015) but1434 Cell Reports 24, 1434–1444, August 7, 2018 a 2018 The Authors
13 high-confidence ESR1 fusion transcripts were identified in 10 ER+ samples from the The Cancer Genome Atlas (TCGA) dataset (Table S1)
Bone and hepatic micrometastases were not observed. Pulmonary metastasis in this model was not a feature of YFP control cells, even when disease burden was increased markedly with E2 supplementation. These results suggest a role for active YAP1 and PCDH11X fusions in driving pulmonary metastasis in association with the expression of genes known to contribute to epithelial-to-mesenchymal transition (EMT) biology and metastatic behavior
Summary
1434 Cell Reports 24, 1434–1444, August 7, 2018 a 2018 The Authors Includes acquired somatic mutations within the ligand-binding domain (LBD) of the estrogen receptor gene (ESR1) causing ligand-independent activation (Pejerrey et al, 2018). RNA sequencing (RNA-seq) has identified multiple ESR1 gene fusion events, but their role in endocrine therapy resistance and how they might be targeted therapeutically is unclear (Giltnane et al, 2017). The majority of ESR1 fusion transcripts have been identified in primary breast cancer, and in some of these instances patients have high-grade disease and/or resistance to endocrine therapy (Giltnane et al, 2017; Veeraraghavan et al, 2014), implying some functionality. Detailed characterization of the predicted chimeric proteins and a clear demonstration of a causal role for ESR1 fusions in endocrine therapy resistance have been largely lacking
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
