|Title||Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Lei, 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|
|Date Published||2018 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 Journal||Cell Rep|