BioProject

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We observed that a subset of Luminal A primary breast tumors 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 drives this subtype switching. To evaluate this, we developed two FGFR4 signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis 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 a treatment options for FGFR4-positive patients, whose high expression is non-genetically determined. Overall design: There are 41 samples in this set. We analyzed 4 replicates of MCF7 and 4 replicates of T47D (both cell lines used as FGFR4 control group: low FGFR4 gene expression) plus 9 replicates of MCF7_FGFR4 and 4 replicates of T47D_FGFR4 (both cell lines used as FGFR4 Active group: high FGFR4 gene expression). As a second approach, we used 6 replicates of CAMA-1 and 4 replicates of MDA-MB-453 (both cell lines used as a FGFR4 Active group: high FGFR4 gene expression) and finally 6 replicates of CAMA-1 and 5 replicates of MDA-M-453 cell lines both treated with BLU9931 (both cell lines were used as control group: low FGFR4 gene expression).