Hotspot ESR1 Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis.
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Authors
Li, Zheqi
Wu, Yang
Yates, Megan E
Tasdemir, Nilgun
Bahreini, Amir
Chen, Jian
Priedigkeit, Nolan M
Nasrazadani, Azadeh
Buluwela, Laki
Gertz, Jason
Troness, Benjamin
El-Ashry, Dorraya
Zhang, Qiang
Zhang, Youbin
Cristofanilli, Massimo
Montanez, Maritza A
Sundd, Prithu
Wallace, Callen T
Watkins, Simon C
Fumagalli, Caterina
Tseng, George C
Wagle, Nikhil
Carroll, Jason S
Karsten, Maria M
Blohmer, Jens-Uwe
Park, Ben H
Publication Date
2022-04-01Journal Title
Cancer Res
ISSN
0008-5472
Publisher
American Association for Cancer Research (AACR)
Pages
canres.can-21-2576-e.2021
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Li, Z., Wu, Y., Yates, M. E., Tasdemir, N., Bahreini, A., Chen, J., Levine, K. M., et al. (2022). Hotspot ESR1 Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis.. Cancer Res, canres.can-21-2576-e.2021. https://doi.org/10.1158/0008-5472.CAN-21-2576
Abstract
UNLABELLED: 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. SIGNIFICANCE: Context- and allele-dependent transcriptome and cistrome reprogramming in mutant ESR1 cell models elicit diverse metastatic phenotypes related to cell adhesion and migration, which can be pharmacologically targeted in metastatic breast cancer.
Sponsorship
Cancer Research UK (C14303/A17197)
Cancer Research UK (C9545/A29580_do not transfer)
Identifiers
External DOI: https://doi.org/10.1158/0008-5472.CAN-21-2576
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334612
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