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

Autores de INCLIVA

• Octavio Burgues Gasion

  Autor

• 

  Ana Lluch Hernández

  Autor

Participantes ajenos a INCLIVA

• 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
• Galvan, Patricia
• Fan, Cheng
• Selitsky, Sara R
• Coffey, Alisha R
• Marron, David
• Braso-Maristany, Fara
• Albanell, Joan
• Rojo, Federico
• Martinez de Duenas, Eduardo
• Rosen, Jeffrey M
• Johnson, Gary L
• Carey, Lisa A
• Prat, Aleix
• Perou, Charles M

Grupos y Plataformas de I+D+i

• Grupo de Investigación en Biología en Cáncer de mama

  

  Leading Researcher

  Pilar Eroles Asensio

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 to 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 FGFR4 likely participates in this subtype switching. To evaluate this, we developed two FGFR4 genomic signatures using a PDX model treated with a FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single cell RNAseq demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the METABRIC breast cancer cohort,FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage. 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 treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.

© 2020, American Society for Clinical Investigation

Keywords

• Breast cancer; Genetics; Oncology