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 5

Prognostic value of FGFR4-derived signatures.

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Prognostic value of FGFR4-derived signatures. (A) Average expression of ...
(A) Average expression of FGFR4-related signatures in TCGA tumor molecular subtypes. Normal-like patients and true-normal tissues have been removed from the analysis. Statistical differences were calculated by ANOVA test. (B) Scatterplot showing the correlation between FGFR4-related signatures and luminal tumor score (LTS) (as calculated in TCGA data set using only HER2E, luminal A, and luminal B tumors). Correlation was measured using the Pearson correlation coefficient. (C) Average expression of FGFR4-related signatures depending on histological tumor grade in METABRIC data (Grade 1: Low grade or well differentiated; Grade 2: Intermediate grade or moderately differentiated; Grade 3: High grade or poorly differentiated). (D and E) Kaplan-Meier plots to test the prognostic ability of FGFR4 signatures in METABRIC (D) and MDACC (E) data sets (normal-like samples were removed from the analysis in both cohorts). Survival curve differences were calculated by the log-rank test and the estimates of survival probabilities and cumulative hazard with a univariate Cox proportional hazards model. (F) Multivariable Cox proportional hazards analyses using METABRIC data (normal-like samples were removed from the analysis). Hazard ratio (HR) = 1: no effect. HR < 1: reduction in hazard. HR > 1: increase in hazard. Signatures were evaluated as continuous variables and rank ordered according to the gene FGFR4 signature scores (induced and repressed) in 3 different levels: low, medium, and high (assigned by distribution in a given upper, middle, or lower tertile). Comparison between more than 2 groups was performed by ANOVA. 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 and data outliers. The whiskers represent the interquartile range. Each mark represents the value of a single sample. LumA, luminal A; LumB, luminal B.