Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer

Adam C. Pond, Jason I. Herschkowitz, Kaylee Schwertfeger, Bryan Welm, Yiqun Zhang, Brian York, Robert D. Cardiff, Susan Hilsenbeck, Charles M. Perou, Chad J. Creighton, Richard E. Lloyd, Jeffrey M. Rosen

Research output: Contribution to journalArticle

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Abstract

Fibroblast growth factor (FGF) cooperates with the Wnt/β-catenin pathway to promote mammary tumorigenesis. To investigate the mechanisms involved in FGF/Wnt cooperation, we genetically engineered a model of inducible FGF receptor (iFGFR) signaling in the context of the well-established mouse mammary tumor virus-Wnt-1 transgenic mouse. In the bigenic mice, iFGFR1 activation dramatically enhanced mammary tumorigenesis. Expression microarray analysis did not show transcriptional enhancement of Wnt/β-catenin target genes but instead showed a translational gene signature that also correlated with elevated FGFR1 and FGFR2 in human breast cancer data sets. Additionally, iFGFR1 activation enhanced recruitment of RNA to polysomes, resulting in a marked increase in protein expression of several different Wnt/β-catenin target genes. FGF pathway activation stimulated extracellular signal-regulated kinase and the phosphorylation of key translation regulators both in vivo in the mouse model and in vitro in a human breast cancer cell line. Our results suggest that cooperation of the FGF and Wnt pathways in mammary tumorigenesis is based on the activation of protein translational pathways that result in, but are not limited to, increased expression of Wnt/β-catenin target genes (at the level of protein translation). Further, they reveal protein translation initiation factors as potential therapeutic targets for human breast cancers with alterations in FGF signaling.

Original languageEnglish (US)
Pages (from-to)4868-4879
Number of pages12
JournalCancer Research
Volume70
Issue number12
DOIs
StatePublished - Jun 15 2010

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Mouse mammary tumor virus
Fibroblast Growth Factor Receptors
Fibroblast Growth Factors
Oncogene Proteins
Catenins
Carcinogenesis
Breast Neoplasms
Wnt Signaling Pathway
Breast
Genes
Translational Peptide Chain Initiation
Peptide Initiation Factors
Polyribosomes
Extracellular Signal-Regulated MAP Kinases
Protein Biosynthesis
Microarray Analysis
Transgenic Mice
Proteins
Phosphorylation
RNA

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Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer. / Pond, Adam C.; Herschkowitz, Jason I.; Schwertfeger, Kaylee; Welm, Bryan; Zhang, Yiqun; York, Brian; Cardiff, Robert D.; Hilsenbeck, Susan; Perou, Charles M.; Creighton, Chad J.; Lloyd, Richard E.; Rosen, Jeffrey M.

In: Cancer Research, Vol. 70, No. 12, 15.06.2010, p. 4868-4879.

Research output: Contribution to journalArticle

Pond, AC, Herschkowitz, JI, Schwertfeger, K, Welm, B, Zhang, Y, York, B, Cardiff, RD, Hilsenbeck, S, Perou, CM, Creighton, CJ, Lloyd, RE & Rosen, JM 2010, 'Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer', Cancer Research, vol. 70, no. 12, pp. 4868-4879. https://doi.org/10.1158/0008-5472.CAN-09-4404
Pond, Adam C. ; Herschkowitz, Jason I. ; Schwertfeger, Kaylee ; Welm, Bryan ; Zhang, Yiqun ; York, Brian ; Cardiff, Robert D. ; Hilsenbeck, Susan ; Perou, Charles M. ; Creighton, Chad J. ; Lloyd, Richard E. ; Rosen, Jeffrey M. / Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer. In: Cancer Research. 2010 ; Vol. 70, No. 12. pp. 4868-4879.
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