Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 9, Pages 4871-4887Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI130323
Keywords
-
Categories
Funding
- National Cancer Institute (NCI) Breast SPORE program [P50-CA58223]
- NCI [R01-CA148761, R01-CA195740, F32-CA210427]
- Breast Cancer Research Foundation
- Susan G. Komen grants [SAC-160074, PDF17479425]
- Fundacion Cientifica Asociacion Espanola Contra el Cancer (AECC) [17-1062]
- Instituto de Salud Carlos III [PI16/00904, PI19/01846]
- AACR Career Development Awards for Translational Breast Cancer Research
- Breast Cancer Now [2018NovPCC1294]
- European Union's Horizon 2020 and innovation programme (H2020-SC1-BHC-2018-2020)
- Fundacio La Marato TV3 [201935-30]
- Fundacion Mutua Madrilena
- Fundacion Quiron-Salud
- Breast Cancer Research Foundation [19-20-26-PRAT]
Ask authors/readers for more resources
Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER . tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available