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FGFR2

Saturday 22 November 2003

Regulation

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.

Pathology

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.

- 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

- common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 are associated with increased breast cancer risks in the general population. (18355772)

  • The fibroblast growth factor receptor 2 (FGFR2) locus has been consistently identified as a breast cancer risk locus in independent genome-wide association studies. (24043118)
  • FGFR2-regulated genes are preferentially linked to breast cancer risk loci in expression quantitative trait loci analysis, supporting the concept that risk genes cluster in pathways.
  • Using a network derived from 2,000 transcriptional profiles, authors identify SPDEF, ERα, FOXA1, GATA3 and PTTG1 as master regulators of fibroblast growth factor receptor 2 signalling, and show that ERα occupancy responds to fibroblast growth factor receptor 2 signalling. (24043118)
  • ERα, FOXA1 and GATA3 contribute to the regulation of breast cancer susceptibility genes, which is consistent with the effects of anti-oestrogen treatment in breast cancer prevention.
  • It suggests that fibroblast growth factor receptor 2 signalling has an important role in mediating breast cancer risk. (24043118)

- 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

- FGFRs

References

- Master regulators of FGFR2 signalling and breast cancer risk. Fletcher MN, Castro MA, Wang X, de Santiago I, O’Reilly M, Chin SF, Rueda OM, Caldas C, Ponder BA, Markowetz F, Meyer KB. Nat Commun. 2013 Sep 17;4:2464. doi : 10.1038/ncomms3464 PMID: 24043118

- FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies. Katoh M. J Invest Dermatol. 2009 Aug;129(8):1861-7. PMID: 19387476

- 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

- Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 2006 Dec 1;66(23):11271-8. PMID: 17145872

- 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