The fibroblast growth factor pathway is known to cooperate with the Wnt/B-catenin pathway in mouse mammary tumorigenesis, and both of these pathways have been implicated in the etiology of human breast cancer. Despite this evidence, little is known about the molecular mechanism contributing to FGF/Wnt pathway cooperation. To investigate the mechanisms involved in this cooperativity, we used genetically engineered mice expressing a drug-inducible model for FGF Receptor signaling (iFGFR) crossed with the well-characterized MMTV-Wnt-1 mouse model. In these bigenic mice, iFGFR1 activation resulted in a dramatic enhancement of mammary tumorigenesis. Tumor microarray analysis did not reveal transcriptional enhancement of Wnt/B-catenin targets, but instead identified a protein translational gene signature that also correlated with elevated FGFR1 and FGFR2 expression in several human breast cancer data sets. Additionally, iFGFR1 activation resulted in enhanced polysome recruitment and a marked increase in protein expression of several different Wnt/B-catenin target oncogenes. Rapid FGFR1-induced ERK activation and phosphorylation of key translation regulators was observed both in vivo in the transgenic mouse model, and in a human breast cancer cell line treated with exogenous FGF. These studies suggest that translational regulation is a key rate-limiting step required for oncogenic cooperativity between the Wnt and FGF pathways. These results not only demonstrate the oncogenic potential of FGFR1 signaling, but also highlight a possible mode of cooperation between FGF and Wnt signaling, involving synergism between two fundamental levels of gene regulation, transcription and translation. FGFRs, provide drugable targets for adjuvant therapy and several known FGFR inhibitors are currently in clinical trials. Additionally, key downstream regulators of translation initiation may also serve as potential therapeutic targets for breast cancers with enhanced FGF signaling.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 282.