title: FGFR4 polymorphic variants modulate phenotypic features of Cushing disease.
abstract: Cushing disease is a potentially lethal condition resulting from hormone excess, usually due to a small pituitary tumor that fails to respond to negative feedback inhibition. A minority of patients develop larger, more aggressive tumors of the same lineage but with modest hormone excess. Here we show that a common polymorphism in the fibroblast growth factor receptor 4 (FGFR4) transmembrane domain yields receptor isoforms with distinct properties that mediate these biological differences. Forced expression of the major FGFR4-G388 variant allele supports pY-signal transducer and activator of transcription (STAT3) responses. In contrast, expression of the minor FGFR4-R388 allele enhances STAT3 serine phosphorylation, driving cellular growth. In addition, FGFR4-R388 enhances glucocorticoid receptor phosphorylation and nuclear translocation. Consistent with these findings, glucocorticoid administration resulted in enhanced hormone negative feedback in mice with knock-in of the FGFR4 variant allele. Moreover, clinical data from patients with pituitary tumors revealed that those homozygous for the R388 allele have a higher frequency of silent corticotroph macroadenomas than FGFR4-G388 carriers, who were more likely to have small but hormonally active microadenomas. These findings demonstrate that the FGFR4 transmembrane polymorphic variants can modulate cellular growth and sensitivity to glucocorticoid hormone negative feedback through distinct STAT3 modifications of relevance to the human forms of Cushing disease.
authors.affiliation: Departments of Medicine (T.N.-T., T.T., M.M.H., L.Z., S.E.) and Laboratory Medicine and Pathobiology (T.N.-T., T.T., S.L.A.), University of Toronto, Toronto, Ontario, Canada M5S 2J7; The Endocrine Oncology Site Group (T.N.-T., T.T., S.L.A., S.E.), Princess Margaret Hospital, Toronto, Ontario, Canada M5T 2M9; Ontario Cancer Institute (T.N.-T., T.T., S.L.A., S.E.), University Health Network, Toronto, Ontario, Canada M5G-1X5; Department of Medical Pharmacology (K.Y.), Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, 770-0855, Japan; and Hypothalamic and Pituitary Surgery (S.Y.), Toranomon Hospital, Tokyo 105-0001, Japan.
authors.forename: Tae
authors.initials: T
authors.lastname: Nakano-Tateno
authors.forename: Toru
authors.initials: T
authors.lastname: Tateno
authors.forename: Maw Maw
authors.initials: MM
authors.lastname: Hlaing
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Shozo
authors.initials: S
authors.lastname: Yamada
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
mesh_terms: D000483:Alleles; D000818:Animals; D049109:Cell Proliferation; D025461:Feedback, Physiological; D055879:Gene Knock-In Techniques; D051379:Mice; D010766:Phosphorylation; D047748:Pituitary ACTH Hypersecretion / Q000235:genetics* / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics / Q000473:pathology; D011110:Polymorphism, Genetic; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D050796:STAT3 Transcription Factor; D011333:Pro-Opiomelanocortin; D051499:Receptor, Fibroblast Growth Factor, Type 4