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National Institute of Environmental Health Sciences

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Publication Detail

Title: FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease.

Authors: Garcia-Recio, Susana; Thennavan, Aatish; East, Michael P; Parker, Joel S; Cejalvo, Juan M; Garay, Joseph P; Hollern, Daniel P; He, Xiaping; Mott, Kevin R; Galván, Patricia; Fan, Cheng; Selitsky, Sara R; Coffey, Alisha R; Marron, David; Brasó-Maristany, Fara; Burgués, Octavio; Albanell, Joan; Rojo, Federico; Lluch, Ana; de Dueñas, Eduardo Martinez; Rosen, Jeffery M; Johnson, Gary L; Carey, Lisa A; Prat, Aleix; Perou, Charles M

Published In J Clin Invest, (2020 09 01)

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.

PubMed ID: 32573490 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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