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Epigenetically Controlled Fibroblast Growth Factor Receptor 2 Signaling Imposes on the RAS/BRAF/Mitogen-Activated Protein Kinase Pathway to Modulate Thyroid Cancer Progression

Departments of ¹ Pathology and ² Medicine, and ³ the Ontario Cancer Institute, Princess Margaret Hospital, University Health Network and ⁴ University of Toronto, Toronto, Ontario, Canada and ⁵ Departments of Breast and Thyroid Surgery, Kawasaki Medical School, Okayama, Japan

Requests for reprints: Shereen Ezzat, Ontario Cancer Institute, 610 University Avenue #8-327, Toronto, Ontario, Canada, M5G-2M9. Phone: 416-586-8505; Fax: 416-586-8834; E-mail: shereen.ezzat{at}utoronto.ca.

Fibroblast growth factor (FGF) signals play fundamental roles in development and tumorigenesis. Thyroid cancer is an example of a tumor with nonoverlapping genetic mutations that up-regulate mitogen-activated protein kinase (MAPK). Here, we show that FGF receptor 1 (FGFR1), which is expressed mainly in neoplastic thyroid cells, propagates MAPK activation and promotes tumor progression. In contrast, FGFR2 is down-regulated in neoplastic thyroid cells through DNA promoter methylation. Reexpression of FGFR2 competes with FGFR1 for the immediate substrate FGFR substrate 2 to impede signaling upstream of the BRAF/MAPK pathway. These data unmask an epigenetically controlled FGFR2 signal that imposes precisely on the intragenically modified BRAF/MAPK pathway to modulate thyroid cancer behavior. [Cancer Res 2007;67(11):5461–70]

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