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+) 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+ patient-derived xenografts and in 55 ERα+ 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 28, 2021
- Source ID
- 10.1158/0008-5472.can-21-1256
Entities
People
- Adrian V Lee
- Airi Han
- Alana L Welm
- Beom-jun Kim
- Charles E Foulds
- Dan R. Robinson
- Diana Fandino
- Harshavardhan Doddapaneni
- Jianhong Hu
- Jonathan T. Lei
- Lacey E. Dobrolecki
- Matthew J Ellis
- Meenakshi Anurag
- Michael T. Lewis
- Nicholas Mitsiades
- Purba Singh
- Saif Rehman
- Shunqiang Li
- Sinem Şeker
- Viktoriya Korchina
- Xuxu Gou
Organizations
- Adrienne Helis Malvin Medical Research Foundation
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute
- National Institute of General Medical Sciences
- Susan G. Komen for the Cure
- United States Department of Defense
- University of Cambridge
- University of Michigan
- University of Pittsburgh
- University of Utah
- Washington University School of Medicine
- Yonsei University