title: The FGFR4-G388R polymorphism promotes mitochondrial STAT3 serine phosphorylation to facilitate pituitary growth hormone cell tumorigenesis.
abstract: Pituitary tumors are common intracranial neoplasms, yet few germline abnormalities have been implicated in their pathogenesis. Here we show that a single nucleotide germline polymorphism (SNP) substituting an arginine (R) for glycine (G) in the FGFR4 transmembrane domain can alter pituitary cell growth and hormone production. Compared with FGFR4-G388 mammosomatotroph cells that support prolactin (PRL) production, FGFR4-R388 cells express predominantly growth hormone (GH). Growth promoting effects of FGFR4-R388 as evidenced by enhanced colony formation was ascribed to Src activation and mitochondrial serine phosphorylation of STAT3 (pS-STAT3). In contrast, diminished pY-STAT3 mediated by FGFR4-R388 relieved GH inhibition leading to hormone excess. Using a knock-in mouse model, we demonstrate the ability of FGFR4-R385 to promote GH pituitary tumorigenesis. In patients with acromegaly, pituitary tumor size correlated with hormone excess in the presence of the FGFR4-R388 but not the FGFR4-G388 allele. Our findings establish a new role for the FGFR4-G388R polymorphism in pituitary oncogenesis, providing a rationale for targeting Src and STAT3 in the personalized treatment of associated disorders.
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, Canada.
authors.forename: Toru
authors.initials: T
authors.lastname: Tateno
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Thomas
authors.initials: T
authors.lastname: Mayr
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000069439:Dasatinib; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D016391:Genes, src; D013006:Growth Hormone / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011388:Prolactin / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D012694:Serine / Q000235:genetics* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013844:Thiazoles; D012694:Serine; D011388:Prolactin; D013006:Growth Hormone; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000069439:Dasatinib