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Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer. 2018
Jonathan T Lei, and
Jieya Shao, and
Jin Zhang, and
Michael Iglesia, and
Doug W Chan, and
Jin Cao, and
Meenakshi Anurag, and
Purba Singh, and
Xiaping He, and
Yoshimasa Kosaka, and
Ryoichi Matsunuma, and
Robert Crowder, and
Jeremy Hoog, and
Chanpheng Phommaly, and
Rodrigo Goncalves, and
Susana Ramalho, and
Raquel Mary Rodrigues Peres, and
Nindo Punturi, and
Cheryl Schmidt, and
Alex Bartram, and
Eric Jou, and
Vaishnavi Devarakonda, and
Kimberly R Holloway, and
W Victoria Lai, and
Oliver Hampton, and
Anna Rogers, and
Ethan Tobias, and
Poojan A Parikh, and
Sherri R Davies, and
Shunqiang Li, and
Cynthia X Ma, and
Vera J Suman, and
Kelly K Hunt, and
Mark A Watson, and
Katherine A Hoadley, and
E Aubrey Thompson, and
Xi Chen, and
Shyam M Kavuri, and
Chad J Creighton, and
Christopher A Maher, and
Charles M Perou, and
Svasti Haricharan, and
Matthew J Ellis
Department of Medicine, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
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.
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