@article{2596cc14aea04781bbe3f0f0cb04de80,
title = "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. Lei et al. show that transcriptionally active estrogen receptor gene (ESR1) fusions identified from late-stage, treatment-refractory estrogen receptor-positive (ER+) breast cancer drive pan-endocrine therapy resistance and metastatic progression. Growth of breast tumors driven by ESR1 fusions at primary and metastatic sties can be suppressed with a CDK4/6 inhibitor.",
keywords = "EMT, ESR1 fusions, PDX, breast cancer, endocrine therapy resistance, metastasis",
author = "Lei, {Jonathan T.} and Jieya Shao and Jin Zhang and Michael Iglesia and Chan, {Doug W.} 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 Peres, {Raquel Mary Rodrigues} and Nindo Punturi and Cheryl Schmidt and Alex Bartram and Eric Jou and Vaishnavi Devarakonda and Holloway, {Kimberly R.} and Lai, {W. Victoria} and Oliver Hampton and Anna Rogers and Ethan Tobias and Parikh, {Poojan A.} and Davies, {Sherri R.} and Shunqiang Li and Ma, {Cynthia X.} and Suman, {Vera J.} and Hunt, {Kelly K.} and Watson, {Mark A.} and Hoadley, {Katherine A.} and Thompson, {E. Aubrey} and Xi Chen and Kavuri, {Shyam M.} and Creighton, {Chad J.} and Maher, {Christopher A.} and Perou, {Charles M.} and Svasti Haricharan and Ellis, {Matthew J.}",
note = "Funding Information: This work is supported by a Susan G. Komen Promise Grant (PG12220321 to M.J.E.), a Susan G. Komen for the Cure grant (KG090422 to S.L.), Susan G. Komen Career Catalyst Grants (CCR14300139 to J.S., CCR16380599 to S.M.K., and CCR14301279 to C.A.M.), a Cancer Prevention Institute of Texas (CPRIT) Recruitment of Established Investigators Award (RR140033 to M.J.E.), the AVON Foundation and the McNair Foundation (both to M.J.E.), the Breast Cancer Research Foundation (BCRF ELFF-16-003 to M.J.E., C.M.P., and E.A.T.), the Department of Defense (W81XWH-12-1-0128 to R.C.), National Cancer Institute of the NIH awards U10-CA180882 to the Alliance for Clinical Trials in Oncology, U24-CA114736 to Monica M. Bertagnolli for support of the Z1031 clinical trial, and U24-CA196171 for Z1031 biospecimen banking, U24-CA143848 to C.M.P. for support of TCGA Breast Cancer Project, NCI Breast SPORE program P50-CA58223 to C.M.P., R01-CA095614 to M.J.E., R00-CA149182 and R21-CA185983 to C.A.M., and T32-GM088129 to J.T.L. We thank Dr. Irwin Gelman (Roswell Park Cancer Institute) for providing the AKAP12 construct, Drs. Beom-Jun Kim and Anna Malovannaya for mass spectrometry analyses, and Dr. Eric C. Chang for helpful discussions (all from Baylor College of Medicine). Funding Information: This work is supported by a Susan G. Komen Promise Grant ( PG12220321 to M.J.E.), a Susan G. Komen for the Cure grant ( KG090422 to S.L.), Susan G. Komen Career Catalyst Grants ( CCR14300139 to J.S., CCR16380599 to S.M.K., and CCR14301279 to C.A.M.), a Cancer Prevention Institute of Texas (CPRIT) Recruitment of Established Investigators Award ( RR140033 to M.J.E.), the AVON Foundation and the McNair Foundation (both to M.J.E.), the Breast Cancer Research Foundation (BCRF ELFF-16-003 to M.J.E., C.M.P., and E.A.T.), the Department of Defense ( W81XWH-12-1-0128 to R.C.), National Cancer Institute of the NIH awards U10-CA180882 to the Alliance for Clinical Trials in Oncology, U24-CA114736 to Monica M. Bertagnolli for support of the Z1031 clinical trial, and U24-CA196171 for Z1031 biospecimen banking, U24-CA143848 to C.M.P. for support of TCGA Breast Cancer Project, NCI Breast SPORE program P50-CA58223 to C.M.P., R01-CA095614 to M.J.E., R00-CA149182 and R21-CA185983 to C.A.M., and T32-GM088129 to J.T.L. We thank Dr. Irwin Gelman (Roswell Park Cancer Institute) for providing the AKAP12 construct, Drs. Beom-Jun Kim and Anna Malovannaya for mass spectrometry analyses, and Dr. Eric C. Chang for helpful discussions (all from Baylor College of Medicine). Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = aug,
day = "7",
doi = "10.1016/j.celrep.2018.07.009",
language = "English (US)",
volume = "24",
pages = "1434--1444.e7",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}