FGFR4 polymorphic variants modulate phenotypic features of Cushing disease
Tae Nakano-Tateno1, Toru Tateno, Maw Maw Hlaing
1Departments 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.
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.
Insights
A common gene variant in fibroblast growth factor receptor 4 (FGFR4) influences pituitary tumor growth and hormone regulation. This discovery offers new insights into Cushing disease, impacting patient outcomes and treatment strategies.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Cushing disease, caused by hormone excess from pituitary tumors, presents variable clinical behaviors.
- Tumor aggressiveness and hormone secretion levels differ among patients, suggesting underlying genetic factors.
- Fibroblast growth factor receptor 4 (FGFR4) is implicated in cellular processes relevant to tumor development.
Purpose of the Study:
- To investigate the role of FGFR4 transmembrane domain polymorphisms in Cushing disease pathogenesis.
- To determine how different FGFR4 variants affect pituitary tumor cell growth and hormone feedback mechanisms.
- To correlate FGFR4 genotypes with clinical presentation and tumor characteristics in patients.
Main Methods:
- Analysis of FGFR4 transmembrane domain polymorphisms and their functional effects on receptor signaling.
- Assessment of signal transducer and activator of transcription (STAT3) phosphorylation and glucocorticoid receptor activity.
- Evaluation of hormone negative feedback in mouse models with specific FGFR4 alleles.
- Correlation of FGFR4 genotypes with pituitary tumor types and clinical data from patients.
Main Results:
- The FGFR4-G388 variant supports STAT3 phosphorylation on tyrosine, while the FGFR4-R388 variant enhances STAT3 serine phosphorylation, promoting cellular growth.
- FGFR4-R388 also increases glucocorticoid receptor phosphorylation and nuclear translocation, potentially affecting hormone feedback.
- Mice with the FGFR4 variant allele showed enhanced glucocorticoid negative feedback.
- Patients homozygous for FGFR4-R388 had a higher incidence of silent corticotroph macroadenomas, whereas G388 carriers were more prone to hormonally active microadenomas.
Conclusions:
- FGFR4 transmembrane polymorphic variants significantly influence cellular growth and glucocorticoid hormone feedback sensitivity.
- Distinct STAT3 modifications mediated by FGFR4 variants are relevant to the pathogenesis of human Cushing disease.
- FGFR4 genotype may serve as a biomarker for predicting pituitary tumor behavior and clinical outcomes in Cushing disease.
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