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

TitleFunctional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.
Publication TypeJournal Article
Year of Publication2018
AuthorsLei, JT, Shao, J, Zhang, J, Iglesia, M, Chan, DW, Cao, J, Anurag, M, Singh, P, He, X, Kosaka, Y, Matsunuma, R, Crowder, R, Hoog, J, Phommaly, C, Goncalves, R, Ramalho, S, Peres, RMary Rodri, Punturi, N, Schmidt, C, Bartram, A, Jou, E, Devarakonda, V, Holloway, KR, W Lai, V, Hampton, O, Rogers, A, Tobias, E, Parikh, PA, Davies, SR, Li, S, Ma, CX, Suman, VJ, Hunt, KK, Watson, MA, Hoadley, KA, E Thompson, A, Chen, X, Kavuri, SM, Creighton, CJ, Maher, CA, Perou, CM, Haricharan, S, Ellis, MJ
JournalCell Rep
Date Published2018 Aug 07

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.

Alternate JournalCell Rep
PubMed ID30089255