Fibroblast growth factor receptor (FGFR)2 is regulated on the basis of the balance of FGFs, heparan-sulfate proteoglycans, FGFR2 isoforms, endogenous inhibitors, and microRNAs.
FGFR2 signals cross-talk with hedgehog (SHH), bone morphogenetic protein (BMPs), and other regulatory networks.
Some cases of congenital skeletal disorders with an FGFR2 mutation show skin phenotypes, including acne, cutis gyrata, and acanthosis nigricans.
Gain-of-function mutations or variations of human FGFR2 occur in estrogen receptor-positive breast cancer, diffuse-type gastric cancer, and endometrial uterine cancer.
Oral administration of AZD2171 or Ki23057 inhibits in vivo proliferation of cancer cells with aberrant FGFR2 activation in rodent therapeutic models.
However, loss-of-function mutations of FGFR2 are reported in human melanoma.
Conditional Fgfr2b knockout in the rodent epidermis leads to increased macrophage infiltration to the dermis and adipose tissue, epidermal thickening accompanied by basal-layer dysplasia and parakeratosis, and the promotion of chemically induced squamous-cell carcinoma.
Dysregulation of FGFR2 results in a spectrum of bone and skin pathologies and several types of cancer.
Pathology
germline FGFR2 mutations in
-
craniosynostoses
- Pfeiffer syndrome
- Crouzon syndrome
- Jackson-Weiss syndrome
- Antley-Bixler syndrome (MIM.207410) (also caused by POR deficiency)
- Apert syndrome
frequent activating FGFR2 mutations in endometrial carcinomas (17525745)
gene amplification
- gastric adenocarcinoma (stomach cancer)
- mammary adenocarcinoma (breast cancer)
common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 are associated with increased breast cancer risks in the general population. (18355772)
bFGF, FGFR1, and FGFR2 are frequently overexpressed in squamous cell carcinoma and adenocarcinoma of the lung. (18829480)
- bFGF signaling pathway activation may be an early phenomenon in the pathogenesis of squamous cell carcinoma and thus an attractive novel target for lung cancer chemopreventive and therapeutic strategies. (18829480)
Mutants
FGFR2-W290C mutationin craniosynostosis and congenital tracheal anomalies (18618990)
See also
References
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FGFR2 as a molecular target in endometrial cancer. Byron SA, Pollock PM. Future Oncol. 2009 Feb;5(1):27-32. PMID: 19243295
FGFR2-related pathogenesis and FGFR2-targeted therapeutics (Review). Katoh Y, Katoh M. Int J Mol Med. 2009 Mar;23(3):307-11. PMID: 19212647
Cancer genomics and genetics of FGFR2 (Review). Katoh M. Int J Oncol. 2008 Aug;33(2):233-7. PMID: 18636142
Roles of FGFR2 and twist in human craniosynostosis: insights from genetic mutations in cranial osteoblasts. Marie PJ, Kaabeche K, Guenou H. Front Oral Biol. 2008;12:144-59. PMID: 18391499
Pollock PM, Gartside MG, Dejeza LC, Powell MA, Mallon MA, Davies H, Mohammadi M, Futreal PA, Stratton MR, Trent JM, Goodfellow PJ. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene. 2007 May 21; PMID: 17525745
Vairaktaris E, Ragos V, Yapijakis C, Derka S, Vassiliou S, Nkenke E, Yannopoulos A, Spyridonidou S, Vylliotis A, Papakosta V, Loukeri S, Lazaris A, Tesseromatis C, Tsigris C, Patsouris E. FGFR-2 and -3 play an important role in initial stages of oral oncogenesis. Anticancer Res. 2006 Nov-Dec;26(6B):4217-21. PMID: 17201136
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Andreou A, Lamy A, Layet V, Cailliez D, Gobet F, Pfister C, Menard M, Frebourg T. Early-onset low-grade papillary carcinoma of the bladder associated with Apert syndrome and a germline FGFR2 mutation (Pro253Arg). Am J Med Genet A. 2006 Oct 15;140(20):2245-7. PMID: 16969861
Chun K, Siegel-Bartelt J, Chitayat D, Phillips J, Ray PN. FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome. Am J Med Genet. 1998 May 18;77(3):219-24. PMID: 9605588
Wilkie AO. Craniosynostosis : genes and mechanisms. Hum Mol Genet. 1997 ;6(10):1647-56. PMID : 9300656
Park WJ, Meyers GA, Li X, Theda C, Day D, Orlow SJ, Jones MC, Jabs EW. Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Hum Mol Genet. 1995 Jul ;4(7):1229-33. PMID : 8528214