%0 Journal Article %J Cell Rep %D 2018 %T Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer. %A Lei, Jonathan T %A Shao, Jieya %A Zhang, Jin %A Iglesia, Michael %A Chan, Doug W %A Cao, Jin %A Anurag, Meenakshi %A Singh, Purba %A He, Xiaping %A Kosaka, Yoshimasa %A Matsunuma, Ryoichi %A Crowder, Robert %A Hoog, Jeremy %A Phommaly, Chanpheng %A Goncalves, Rodrigo %A Ramalho, Susana %A Peres, Raquel Mary Rodrigues %A Punturi, Nindo %A Schmidt, Cheryl %A Bartram, Alex %A Jou, Eric %A Devarakonda, Vaishnavi %A Holloway, Kimberly R %A Lai, W Victoria %A Hampton, Oliver %A Rogers, Anna %A Tobias, Ethan %A Parikh, Poojan A %A Davies, Sherri R %A Li, Shunqiang %A Ma, Cynthia X %A Suman, Vera J %A Hunt, Kelly K %A Watson, Mark A %A Hoadley, Katherine A %A Thompson, E Aubrey %A Chen, Xi %A Kavuri, Shyam M %A Creighton, Chad J %A Maher, Christopher A %A Perou, Charles M %A Haricharan, Svasti %A Ellis, Matthew J %K Breast Neoplasms %K Estrogen Receptor alpha %K Female %K Gene Fusion %K Humans %K Transfection %X

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.

%B Cell Rep %V 24 %P 1434-1444.e7 %8 2018 Aug 07 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/30089255?dopt=Abstract %R 10.1016/j.celrep.2018.07.009