@article{c2feb6e894554a8781f921431388e929,
title = "Transcriptional Reprogramming Differentiates Active from Inactive ESR1 Fusions in Endocrine Therapy-Refractory Metastatic Breast Cancer",
abstract = "Genomic analysis has recently identified multiple ESR1 gene translocations in estrogen receptor alpha–positive (ERα{\th}) metastatic breast cancer (MBC) that encode chimeric proteins whereby the ESR1 ligand binding domain (LBD) is replaced by C-terminal sequences from many different gene partners. Here we functionally screened 15 ESR1 fusions and identified 10 that promoted estradiol-independent cell growth, motility, invasion, epithelial-to-mesenchymal transition, and resistance to fulvestrant. RNA sequencing identified a gene expression pattern specific to functionally active ESR1 gene fusions that was subsequently reduced to a diagnostic 24-gene signature. This signature was further examined in 20 ERα{\th} patient-derived xenografts and in 55 ERα{\th} MBC samples. The 24-gene signature successfully identified cases harboring ESR1 gene fusions and also accurately diagnosed the presence of activating ESR1 LBD point mutations. Therefore, the 24-gene signature represents an efficient approach to screening samples for the presence of diverse somatic ESR1 mutations and translocations that drive endocrine treatment failure in MBC.",
author = "Xuxu Gou and Meenakshi Anurag and Lei, {Jonathan T.} and Kim, {Beom Jun} and Purba Singh and Sinem Seker and Diana Fandino and Airi Han and Saif Rehman and Jianhong Hu and Viktoriya Korchina and Harshavardhan Doddapaneni and Dobrolecki, {Lacey E.} and Nicholas Mitsiades and Lewis, {Michael T.} and Welm, {Alana L.} and Shunqiang Li and Lee, {Adrian V.} and Robinson, {Dan R.} and Foulds, {Charles E.} and Ellis, {Matthew J.}",
note = "Funding Information: X. Gou reports grants from Cancer Prevention and Research Institute of Texas (CPRIT) Training Grant during the conduct of the study; in addition, X. Gou has a patent for 24-gene diagnostic signature pending to BCM. L.E. Dobrolecki reports personal fees from StemMed, Ltd., outside the submitted work. M.T. Lewis reports grants from NCI and CPRIT during the conduct of the study and other support from StemMed Ltd and Tvardi Therapeutics Inc. outside the submitted work. A.L. Welm reports other support from Thunder Biotech, Modulus Therapeutics, Inc., and J. Michael Bishop Institute for Cancer Research outside the submitted work; and A.L. Welm may receive tangible property royalties if University of Utah chooses to license HCI PDX models to for-profit-companies. S. Li reports grants, personal fees, and nonfinancial support from NIH 5U54CA224083 during the conduct of the study and personal fees from Envigo outside the submitted work. C.E. Foulds reports grants from Adrienne Helis Malvin Medical Research Foundation during the conduct of the study; other support from Coactigon, Inc., outside the submitted work; in addition, C.E. Foulds has a patent for 24-gene diagnostic signature pending to BCM. M.J. Ellis reports grants from NCI, Susan G. Komen Foundation, DOD Breast Cancer Research Program, McNair Medical Institute at The Robert and Janice McNair Foundation, CPRIT, and Adrienne Helis Malvin Medical Research Foundation during the conduct of the study; personal fees from Lilly, Novartis, AstraZeneca, Pfizer, Veracyte, Bioclassifier, and Washington University in St Louis outside the submitted work; in addition, M.J. Ellis has a patent for MOTERA signature pending. No disclosures were reported by the other authors. Funding Information: The authors gratefully acknowledge Drs. Bing Zhang and Eric C. Chang at BCM for their scientific input. This work was supported by the following grants to M.J. Ellis from the Susan G. Komen Foundation (SAC190059, PG12220321, SAC130059, and BCTR0707808), the DOD Breast Cancer Research Program Grant (W81XWH-21-1-0119), and National Cancer Institute Grants P50CA186784 and U54CA233223 (to N. Mitsiades and M.J. Ellis) and U54CA224076 to M.T. Lewis and A.L. Welm. M.J. Ellis is also a Susan G. Komen Foundation Scholar, a McNair Scholar supported by the McNair Medical Institute at The Robert and Janice McNair Foundation, and a recipient of a CPRIT Established Investigator Award (RR140027). X. Gou was supported by CPRIT RP210027?Baylor College of Medicine Comprehensive Cancer Training Program. J.T. Lei was supported by T32CA203690 and T32GM088129. This project was also supported in part by the GARP Core at BCM, with funding from the NIH NCI grant (P30CA125123) and the NIH S10 grant (1S10OD023469). The authors also acknowledge the Adrienne Helis Malvin Medical Research Foundation through direct engagement with the continuous active conduct of medical research in conjunction with BCM (M-2017 to C.E. Foulds; M-2020 to M.J. Ellis). The BCM ER? PDXs were generated with a CPRIT Core Facility Support Grant to M.T. Lewis (RP170691) and P30 Cancer Center Support Grant (P30CA125123). Funding Information: The authors gratefully acknowledge Drs. Bing Zhang and Eric C. Chang at BCM for their scientific input. This work was supported by the following grants to M.J. Ellis from the Susan G. Komen Foundation (SAC190059, PG12220321, SAC130059, and BCTR0707808), the DOD Breast Cancer Research Program Grant (W81XWH-21-1-0119), and National Cancer Institute Grants P50CA186784 and U54CA233223 (to N. Mitsiades and M.J. Ellis) and U54CA224076 to M.T. Lewis and A.L. Welm. M.J. Ellis is also a Susan G. Komen Foundation Scholar, a McNair Scholar supported by the McNair Medical Institute at The Robert and Janice McNair Foundation, and a recipient of a CPRIT Established Investigator Award (RR140027). X. Gou was supported by CPRIT RP210027—Baylor College of Medicine Comprehensive Cancer Training Program. J.T. Lei was supported by T32CA203690 and T32GM088129. This project was also supported in part by the GARP Core at BCM, with funding from the NIH NCI grant (P30CA125123) and the NIH S10 grant (1S10OD023469). The authors also acknowledge the Adrienne Helis Malvin Medical Research Foundation through direct engagement with the continuous active conduct of medical research in conjunction with BCM (M-2017 to C.E. Foulds; M-2020 to M.J. Ellis). The BCM ER+PDXs were generated with a CPRIT Core Facility Support Grant to M.T. Lewis (RP170691) and P30 Cancer Center Support Grant (P30CA125123). Publisher Copyright: {\textcopyright}2021 The Authors",
year = "2021",
month = dec,
day = "15",
doi = "10.1158/0008-5472.CAN-21-1256",
language = "English",
volume = "81",
pages = "6259--6272",
journal = "Cancer Research",
issn = "0008-5472",
number = "24",
}