FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease
Mostra el registre complet Registre parcial de l'ítem
- dc.contributor.author Garcia-Recio, Susana
- dc.contributor.author Albanell Mestres, Joan
- dc.contributor.author Perou, Charles M.
- dc.date.accessioned 2021-10-13T06:52:03Z
- dc.date.available 2021-10-13T06:52:03Z
- dc.date.issued 2020
- dc.description.abstract 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.
- dc.format.mimetype application/pdf
- dc.identifier.citation Garcia-Recio S, Thennavan A, East MP, Parker JS, Cejalvo JM, Garay JP, et al. FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease. J Clin Invest. 2020 Sep 1;130(9):4871-87. DOI: 10.1172/JCI130323
- dc.identifier.doi http://dx.doi.org/10.1172/JCI130323
- dc.identifier.issn 0021-9738
- dc.identifier.uri http://hdl.handle.net/10230/48640
- dc.language.iso eng
- dc.publisher American Society for Clinical Investigation
- dc.rights © American Society for Clinical Investigation http://dx.doi.org/10.1172/JCI130323
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.subject.keyword Breast cancer
- dc.subject.keyword Genetics
- dc.subject.keyword Oncology
- dc.title FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion