FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease
Susana Garcia-Recio, … , Aleix Prat, Charles M. Perou
Susana Garcia-Recio, … , Aleix Prat, Charles M. Perou
Published June 23, 2020
Citation Information: J Clin Invest. 2020;130(9):4871-4887. https://doi.org/10.1172/JCI130323.
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Research Article Genetics Oncology

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

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.

Authors

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

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Figure 2

Testing the impact of FGFR4 on tumor growth and tumor differentiation in a HER2E/cHER2– PDX (WHIM11).

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Testing the impact of FGFR4 on tumor growth and tumor differentiation in...
(A) Tumor growth and (B) tumor weight of WHIM11 tumors treated with BLU9931 (0.6 g/kg/day) or lapatinib (1.833 g/kg/day) for approximately 18 days (5 animals per treatment arm). Data represent mean tumor volume ± SEM. (C) Correlation to the PAM50 centroids (basal, HER2E, luminal A, luminal B) of mice treated with BLU9931 and untreated mice. (D) BLU9931-treated, lapatinib-treated, or untreated tumors evaluated for a luminal tumor score (LTS) tested along with TGCA cohort grouped according to intrinsic subtype. (E and F) Supervised hierarchical cluster across 1100 breast tumors and 98 normal samples from TCGA data set using FGFR4-related signatures. Significantly upregulated genes defined as an FGFR4-repressed signature (E) and significantly downregulated genes defined as a FGFR4-induced signature (F). Each gene set or subcluster has been selected based on a node correlation greater than 0.5 and named according to the important biological process governed by it as identified by Gene Ontology. Comparison between more than 2 groups was performed by ANOVA with post hoc Tukey’s test: *P < 0.05; **P < 0.01; ***P < 0.001. Statistically significant values are highlighted in red. Box-and-whisker plots display the median value on each bar, showing the lower and upper quartile range of the data. The whiskers represent the interquartile range.