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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.
Highlights
Pituitary tumors occur in almost 20% of the population [1] and represent nearly 10% of surgically resected intracranial tumors [2,3]
We show that a frequent single nucleotide polymorphism (SNP) associated with increased cancer risk and progression deregulates pituitary function
These findings provide an example of a potentially common genetic program shared between cancer and a hormone that promotes its progression. These studies were all carried out with the prototypic receptor prior to the identification of a single nucleotide polymorphism (SNP) that alters the coding region of the transmembrane domain. This germ-line polymorphism substitutes a glycine with an arginine at codon 388 of FGFR4, resulting in a charged amino acid in the highly conserved and normally hydrophobic transmembrane region of the receptor [21]
Summary
Pituitary tumors occur in almost 20% of the population [1] and represent nearly 10% of surgically resected intracranial tumors [2,3]. They can cause significant health problems due to abnormal hormone production and invasion into surrounding brain structures [2,3]. Germline genetic abnormalities associated with pituitary tumor pathogenesis include inactivating mutations of menin in patients with Multiple Endocrine Neoplasia type 1 [6,7], loss of function mutations of the aryl hydrocarbon receptor-interacting protein (AIP) tumor suppressor gene in patients with familial isolated pituitary adenomas [8], and activating mutations the Protein kinase A type I regulatory subunit PRKA [9] in patients with Carney complex, these alterations have not been shown to mediate pituitary neoplastic growth in the more common sporadic neoplasms. FGF-2, originally described in bovine pituitary folliculostellate cells, regulates multiple pituitary hormones and is over-expressed by human pituitary adenomas tumors [15]
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