HotspotESR1Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis
Abstract
Constitutively active estrogen receptor α (ER/ESR1) mutations have been identified in approximately one-third of ER+ metastatic breast cancers. Although these mutations are known as mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1-mutant tumors, genome-edited ESR1 Y537S and D538G-mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell–cell contacts while decreasing cell-extracellular matrix adhesion. In vivo studies showed ESR1-mutant cells were associated with larger multicellular circulating tumor cell (CTC) clusters with increased compactness compared with ESR1 wild-type CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, context-dependent migratory phenotypes revealed cotargeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited noncanonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation–modulated metastasis and suggest future therapeutic strategies for targeting ESR1-mutant breast cancer.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 25, 2022
- Source ID
- 10.1158/0008-5472.can-21-2576
Entities
People
- Adrian V Lee
- Amir Bahreini
- Azadeh Nasrazadani
- Ben H. Park
- Benjamin Troness
- Callen T Wallace
- Carsten Denkert
- Caterina Fumagalli
- Dorraya El-ashry
- Elena Guerini-Rocco
- George C. Tseng
- Jason Gertz
- Jason S. Carroll
- Jennifer K Richer
- Jennifer M Atkinson
- Jens-uwe Blohmer
- Jian Chen
- Kevin M Levine
- Laki Buluwela
- Li Zhu
- Lorenzo Gerratana
- Maria M. Karsten
- Maritza A. Montanez
- Massimo Cristofanilli
- Megan E. Yates
- Nikhil Wagle
- Nilgun Tasdemir
- Nolan M. Priedigkeit
- Paul Jank
- Peter C. Lucas
- Prithu Sundd
- Qiang Zhang
- Simak Ali
- Simon C Watkins
- Spencer Arnesen
- Steffi Oesterreich
- Yang Wu
- Youbin Zhang
- Zheqi Li
Organizations
- European Institute of Oncology
- Freie Universität Berlin
- Harvard Medical School
- Imperial College London
- National Cancer Institute
- National Institutes of Health
- Northwestern University
- Susan G. Komen for the Cure
- The Cancer Center at the University of Minnesota
- Tsinghua University
- United States Department of Defense
- University of Cambridge
- University of Colorado
- University of Marburg
- University of Milan
- University of Pittsburgh
- University of Udine
- University of Utah