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FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease.
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.
Afiliación
  • Garcia-Recio S; Lineberger Comprehensive Center and.
  • Thennavan A; Department of Genetics, School of Medicine.
  • East MP; Lineberger Comprehensive Center and.
  • Parker JS; Oral and Craniofacial Biomedicine Program, School of Dentistry, and.
  • Cejalvo JM; Department of Pharmacology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Garay JP; Lineberger Comprehensive Center and.
  • Hollern DP; Department of Genetics, School of Medicine.
  • He X; Translational Genomics and Targeted Therapeutics in Oncology (IDIBAPS), Barcelona, Spain.
  • Mott KR; Medical Oncology Department, Hospital Clinic, Barcelona, Spain.
  • Galván P; Lineberger Comprehensive Center and.
  • Fan C; Department of Genetics, School of Medicine.
  • Selitsky SR; Lineberger Comprehensive Center and.
  • Coffey AR; Department of Genetics, School of Medicine.
  • Marron D; Lineberger Comprehensive Center and.
  • Brasó-Maristany F; Department of Genetics, School of Medicine.
  • Burgués O; Lineberger Comprehensive Center and.
  • Albanell J; Department of Genetics, School of Medicine.
  • Rojo F; Translational Genomics and Targeted Therapeutics in Oncology (IDIBAPS), Barcelona, Spain.
  • Lluch A; Medical Oncology Department, Hospital Clinic, Barcelona, Spain.
  • de Dueñas EM; Lineberger Comprehensive Center and.
  • Rosen JM; Department of Genetics, School of Medicine.
  • Johnson GL; Lineberger Comprehensive Center and.
  • Carey LA; Lineberger Comprehensive Center and.
  • Prat A; Lineberger Comprehensive Center and.
  • Perou CM; Translational Genomics and Targeted Therapeutics in Oncology (IDIBAPS), Barcelona, Spain.
J Clin Invest ; 130(9): 4871-4887, 2020 09 01.
Article en En | MEDLINE | ID: mdl-32573490
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Regulación Neoplásica de la Expresión Génica / Diferenciación Celular / Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos / Proteínas de Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: J Clin Invest Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Regulación Neoplásica de la Expresión Génica / Diferenciación Celular / Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos / Proteínas de Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: J Clin Invest Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos