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

Abstract

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.

• Authors: Jonathan T Lei, Jieya Shao, Jin Zhang, Michael Iglesia, Doug W Chan, Jin Cao, Meenakshi Anurag, Purba Singh, Xiaping He, Yoshimasa Kosaka, Ryoichi Matsunuma, Robert Crowder, Jeremy Hoog, Chanpheng Phommaly, Rodrigo Goncalves, Susana Ramalho, Raquel Mary Rodrigues Peres, Nindo Punturi, Cheryl Schmidt, Alex Bartram, Eric Jou, Vaishnavi Devarakonda, Kimberly R Holloway, W Victoria Lai, Oliver Hampton, Anna Rogers, Ethan Tobias, Poojan A Parikh, Sherri R Davies, Shunqiang Li, Cynthia X Ma, Vera J Suman, Kelly K Hunt, Mark A Watson, Katherine A Hoadley, E Aubrey Thompson, Xi Chen, Shyam M Kavuri, Chad J Creighton, Christopher A Maher, Charles M Perou, Svasti Haricharan, Matthew J Ellis
• Journal: Cell reports (Cell Rep) Vol. 24 Issue 6 Pg. 1434-1444.e7 (08 07 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 30089255 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha

Topics

• Breast Neoplasms (genetics, pathology)
• Estrogen Receptor alpha (genetics)
• Female
• Gene Fusion (genetics)
• Humans
• Transfection