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

Autor:	Garcia-Recio S; Lineberger Comprehensive Center and.; Department of Genetics, School of Medicine., Thennavan A; Lineberger Comprehensive Center and.; Oral and Craniofacial Biomedicine Program, School of Dentistry, and., East MP; Department of Pharmacology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA., Parker JS; Lineberger Comprehensive Center and.; Department of Genetics, School of Medicine., Cejalvo JM; Translational Genomics and Targeted Therapeutics in Oncology (IDIBAPS), Barcelona, Spain.; Medical Oncology Department, Hospital Clinic, Barcelona, Spain., Garay JP; Lineberger Comprehensive Center and.; Department of Genetics, School of Medicine., Hollern DP; Lineberger Comprehensive Center and.; Department of Genetics, School of Medicine., He X; Lineberger Comprehensive Center and.; Department of Genetics, School of Medicine., Mott KR; Lineberger Comprehensive Center and.; Department of Genetics, School of Medicine., Galván P; Translational Genomics and Targeted Therapeutics in Oncology (IDIBAPS), Barcelona, Spain.; Medical Oncology Department, Hospital Clinic, Barcelona, Spain., Fan C; Lineberger Comprehensive Center and.; Department of Genetics, School of Medicine., Selitsky SR; Lineberger Comprehensive Center and., Coffey AR; Lineberger Comprehensive Center and., Marron D; Lineberger Comprehensive Center and., Brasó-Maristany F; Translational Genomics and Targeted Therapeutics in Oncology (IDIBAPS), Barcelona, Spain.; Medical Oncology Department, Hospital Clinic, Barcelona, Spain., Burgués O; GEICAM, Spanish Breast Cancer Group, Madrid, Spain.; Department of Pathology, Hospital Clínico Universitario de Valencia, Valencia, Spain., Albanell J; GEICAM, Spanish Breast Cancer Group, Madrid, Spain.; Centro de Investigación Biomédica en Red de Oncología (CIBERONC-ISCIII), Madrid, Spain.; IMIM Hospital del Mar Medical Research Institute, Barcelona, Spain.; Medical Oncology Department Hospital del Mar, Barcelona, Spain.; Universitat Pompeu Fabra, Barcelona, Spain., Rojo F; GEICAM, Spanish Breast Cancer Group, Madrid, Spain.; Centro de Investigación Biomédica en Red de Oncología (CIBERONC-ISCIII), Madrid, Spain.; Fundación Jiménez Díaz, Madrid, Spain., Lluch A; GEICAM, Spanish Breast Cancer Group, Madrid, Spain.; Centro de Investigación Biomédica en Red de Oncología (CIBERONC-ISCIII), Madrid, Spain.; Hospital Clínico Universitario de Valencia, Valencia, Spain.; Biomedical Research Institute INCLIVA, Universitat de València, Valencia, Spain., de Dueñas EM; GEICAM, Spanish Breast Cancer Group, Madrid, Spain.; Centro de Investigación Biomédica en Red de Oncología (CIBERONC-ISCIII), Madrid, Spain.; Hospital Provincial de Castellón, Castellón, Spain., Rosen JM; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA., Johnson GL; Department of Pharmacology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA., Carey LA; Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA., Prat A; Translational Genomics and Targeted Therapeutics in Oncology (IDIBAPS), Barcelona, Spain.; Medical Oncology Department, Hospital Clinic, Barcelona, Spain.; SOLTI Breast Cancer Research Group, Barcelona, Spain., Perou CM; Lineberger Comprehensive Center and.; Department of Genetics, School of Medicine.; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2020 Sep 01; Vol. 130 (9), pp. 4871-4887.
DOI:	10.1172/JCI130323
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu