Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer
| Autor: | Vera J. Suman, Katherine A. Hoadley, Xi Chen, Christopher G. Maher, Xiaping He, Shunqiang Li, Doug W. Chan, Yoshimasa Kosaka, Jeremy Hoog, Matthew J. Ellis, Raquel Mary Rodrigues Peres, Purba Singh, Nindo Punturi, Chad J. Creighton, Alex Bartram, Vaishnavi Devarakonda, Robert J. Crowder, Svasti Haricharan, Jonathan T. Lei, Shyam M. Kavuri, Mark A. Watson, Jin Zhang, Rodrigo Franco Gonçalves, Michael D. Iglesia, Jin Cao, Chanpheng Phommaly, E. Aubrey Thompson, Jieya Shao, Cheryl Schmidt, P Parikh, Cynthia X. Ma, Susana Ramalho, Ryoichi Matsunuma, Kimberly R. Holloway, Eric Jou, Kelly K. Hunt, Meenakshi Anurag, W. Victoria Lai, Sherri R. Davies, Ethan Tobias, Anna Rogers, Charles M. Perou, Oliver A. Hampton |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.drug_class Estrogen receptor Breast Neoplasms Biology Transfection Article General Biochemistry Genetics and Molecular Biology Metastasis 03 medical and health sciences Exon medicine Humans lcsh:QH301-705.5 Gene YAP1 Estrogen Receptor alpha medicine.disease Fusion protein 3. Good health body regions 030104 developmental biology lcsh:Biology (General) Estrogen Cancer research Female Gene Fusion Estrogen receptor alpha |
| Zdroj: | Cell Reports, Vol 24, Iss 6, Pp 1434-1444.e7 (2018) Cell reports |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY 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. In Brief Lei et al. show that transcriptionally active estrogen receptor gene (ESR1) fusions identified from late-stage, treatment-refractory estrogen receptor-positive (ER+) breast cancer drive pan-endocrine therapy resistance and metastatic progression. Growth of breast tumors driven by ESR1 fusions at primary and metastatic sties can be suppressed with a CDK4/6 inhibitor. Graphical Abstract |
| Databáze: | OpenAIRE |
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