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. 1992 Aug;66(2):273–280. doi: 10.1038/bjc.1992.256

Expression of basic fibroblast growth factor, FGFR1 and FGFR2 in normal and malignant human breast, and comparison with other normal tissues.

Y A Luqmani 1, M Graham 1, R C Coombes 1
PMCID: PMC1977809  PMID: 1380281

Abstract

The expression of basic fibroblast growth factor (bFGF) and two of its receptors, FGFR1 and FGFR2, was detected using the polymerase chain reaction, and quantified by comparison to the relative amount of product obtained following co-amplification of the ubiquitous glyceraldehyde phosphate dehydrogenase transcript. Varying levels were found in the vast majority of both cancer and non-malignant breast biopsies as well as in samples of several other normal human tissues. Significantly less bFGF was present in cancers (P less than 0.0001). Similarly, FGFR2 product was also much less in cancer tissues (P = 0.0078), as was FGFR1 (P = 0.002). FGFR1 levels in cancers tended to be higher in those which were oestrogen receptor positive (P less than 0.06). Amplification of different coding regions showed evidence of variant forms of FGFR1 RNA. Cancers appeared to have a significantly greater proportion of PCR product corresponding to the region between the third immunoglobulin like domain and the tyrosine kinase domain (P = 0.046). Differential expression was observed in breast cell lines, with bFGF in the normal derived HBL100, HBR SV1.6.1 and 184A1 but little or none in ZR-75-1, MCF-7, T47D and MDA-MB-231. FGFR1 was present in most of these but FGFR2 was absent from T47D, MDA-MB-231 and HBL100. ZR-75-1 cells had a marked preponderance of FGFR1 variants lacking part of the coding sequence. Aberrant receptor processing may provide clues concerning the role of FGF's and their potential involvement in malignancy.

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Selected References

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  1. Abraham J. A., Whang J. L., Tumolo A., Mergia A., Friedman J., Gospodarowicz D., Fiddes J. C. Human basic fibroblast growth factor: nucleotide sequence and genomic organization. EMBO J. 1986 Oct;5(10):2523–2528. doi: 10.1002/j.1460-2075.1986.tb04530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adnane J., Gaudray P., Dionne C. A., Crumley G., Jaye M., Schlessinger J., Jeanteur P., Birnbaum D., Theillet C. BEK and FLG, two receptors to members of the FGF family, are amplified in subsets of human breast cancers. Oncogene. 1991 Apr;6(4):659–663. [PubMed] [Google Scholar]
  3. Arcari P., Martinelli R., Salvatore F. The complete sequence of a full length cDNA for human liver glyceraldehyde-3-phosphate dehydrogenase: evidence for multiple mRNA species. Nucleic Acids Res. 1984 Dec 11;12(23):9179–9189. doi: 10.1093/nar/12.23.9179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baird A., Ueno N., Esch F., Ling N. Distribution of fibroblast growth factors (FGFs) in tissues and structure-function studies with synthetic fragments of basic FGF. J Cell Physiol Suppl. 1987;Suppl 5:101–106. doi: 10.1002/jcp.1041330419. [DOI] [PubMed] [Google Scholar]
  5. Baird A., Walicke P. A. Fibroblast growth factors. Br Med Bull. 1989 Apr;45(2):438–452. doi: 10.1093/oxfordjournals.bmb.a072333. [DOI] [PubMed] [Google Scholar]
  6. Briozzo P., Badet J., Capony F., Pieri I., Montcourrier P., Barritault D., Rochefort H. MCF7 mammary cancer cells respond to bFGF and internalize it following its release from extracellular matrix: a permissive role of cathepsin D. Exp Cell Res. 1991 Jun;194(2):252–259. doi: 10.1016/0014-4827(91)90362-x. [DOI] [PubMed] [Google Scholar]
  7. Burgess W. H., Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem. 1989;58:575–606. doi: 10.1146/annurev.bi.58.070189.003043. [DOI] [PubMed] [Google Scholar]
  8. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  9. Cordon-Cardo C., Vlodavsky I., Haimovitz-Friedman A., Hicklin D., Fuks Z. Expression of basic fibroblast growth factor in normal human tissues. Lab Invest. 1990 Dec;63(6):832–840. [PubMed] [Google Scholar]
  10. Delli Bovi P., Curatola A. M., Kern F. G., Greco A., Ittmann M., Basilico C. An oncogene isolated by transfection of Kaposi's sarcoma DNA encodes a growth factor that is a member of the FGF family. Cell. 1987 Aug 28;50(5):729–737. doi: 10.1016/0092-8674(87)90331-x. [DOI] [PubMed] [Google Scholar]
  11. Dickson C., Peters G. Potential oncogene product related to growth factors. 1987 Apr 30-May 6Nature. 326(6116):833–833. doi: 10.1038/326833a0. [DOI] [PubMed] [Google Scholar]
  12. Dionne C. A., Crumley G., Bellot F., Kaplow J. M., Searfoss G., Ruta M., Burgess W. H., Jaye M., Schlessinger J. Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors. EMBO J. 1990 Sep;9(9):2685–2692. doi: 10.1002/j.1460-2075.1990.tb07454.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Engel L. W., Young N. A. Human breast carcinoma cells in continuous culture: a review. Cancer Res. 1978 Nov;38(11 Pt 2):4327–4339. [PubMed] [Google Scholar]
  14. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  15. Fujita H., Ohta M., Kawasaki T., Itoh N. The expression of two isoforms of the human fibroblast growth factor receptor (flg) is directed by alternative splicing. Biochem Biophys Res Commun. 1991 Jan 31;174(2):946–951. doi: 10.1016/0006-291x(91)91510-j. [DOI] [PubMed] [Google Scholar]
  16. Gomm J. J., Smith J., Ryall G. K., Baillie R., Turnbull L., Coombes R. C. Localization of basic fibroblast growth factor and transforming growth factor beta 1 in the human mammary gland. Cancer Res. 1991 Sep 1;51(17):4685–4692. [PubMed] [Google Scholar]
  17. Gospodarowicz D., Neufeld G., Schweigerer L. Molecular and biological characterization of fibroblast growth factor, an angiogenic factor which also controls the proliferation and differentiation of mesoderm and neuroectoderm derived cells. Cell Differ. 1986 Jul;19(1):1–17. doi: 10.1016/0045-6039(86)90021-7. [DOI] [PubMed] [Google Scholar]
  18. Hattori Y., Odagiri H., Nakatani H., Miyagawa K., Naito K., Sakamoto H., Katoh O., Yoshida T., Sugimura T., Terada M. K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5983–5987. doi: 10.1073/pnas.87.15.5983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hou J. Z., Kan M. K., McKeehan K., McBride G., Adams P., McKeehan W. L. Fibroblast growth factor receptors from liver vary in three structural domains. Science. 1991 Feb 8;251(4994):665–668. doi: 10.1126/science.1846977. [DOI] [PubMed] [Google Scholar]
  20. Jaye M., Howk R., Burgess W., Ricca G. A., Chiu I. M., Ravera M. W., O'Brien S. J., Modi W. S., Maciag T., Drohan W. N. Human endothelial cell growth factor: cloning, nucleotide sequence, and chromosome localization. Science. 1986 Aug 1;233(4763):541–545. doi: 10.1126/science.3523756. [DOI] [PubMed] [Google Scholar]
  21. Johnson D. E., Lu J., Chen H., Werner S., Williams L. T. The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol Cell Biol. 1991 Sep;11(9):4627–4634. doi: 10.1128/mcb.11.9.4627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Keegan K., Johnson D. E., Williams L. T., Hayman M. J. Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1095–1099. doi: 10.1073/pnas.88.4.1095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Klagsbrun M., Sasse J., Sullivan R., Smith J. A. Human tumor cells synthesize an endothelial cell growth factor that is structurally related to basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2448–2452. doi: 10.1073/pnas.83.8.2448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kornbluth S., Paulson K. E., Hanafusa H. Novel tyrosine kinase identified by phosphotyrosine antibody screening of cDNA libraries. Mol Cell Biol. 1988 Dec;8(12):5541–5544. doi: 10.1128/mcb.8.12.5541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lee P. L., Johnson D. E., Cousens L. S., Fried V. A., Williams L. T. Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science. 1989 Jul 7;245(4913):57–60. doi: 10.1126/science.2544996. [DOI] [PubMed] [Google Scholar]
  26. Lehtola L., Partanen J., Sistonen L., Korhonen J., Wärri A., Härkönen P., Clarke R., Alitalo K. Analysis of tyrosine kinase mRNAs including four FGF receptor mRNAs expressed in MCF-7 breast-cancer cells. Int J Cancer. 1992 Feb 20;50(4):598–603. doi: 10.1002/ijc.2910500419. [DOI] [PubMed] [Google Scholar]
  27. Luqmani Y. A., Smith J., Coombes R. C. Polymerase chain reaction-aided analysis of gene expression in frozen tissue sections. Anal Biochem. 1992 Feb 1;200(2):291–295. doi: 10.1016/0003-2697(92)90468-m. [DOI] [PubMed] [Google Scholar]
  28. Marics I., Adelaide J., Raybaud F., Mattei M. G., Coulier F., Planche J., de Lapeyriere O., Birnbaum D. Characterization of the HST-related FGF.6 gene, a new member of the fibroblast growth factor gene family. Oncogene. 1989 Mar;4(3):335–340. [PubMed] [Google Scholar]
  29. Maxwell M., Naber S. P., Wolfe H. J., Hedley-Whyte E. T., Galanopoulos T., Neville-Golden J., Antoniades H. N. Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression. Cancer Res. 1991 Feb 15;51(4):1345–1351. [PubMed] [Google Scholar]
  30. Mira-y-Lopez R., Joseph-Silverstein J., Rifkin D. B., Ossowski L. Identification of a pituitary factor responsible for enhancement of plasminogen activator activity in breast tumor cells. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7780–7784. doi: 10.1073/pnas.83.20.7780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Moscatelli D., Rifkin D. B. Membrane and matrix localization of proteinases: a common theme in tumor cell invasion and angiogenesis. Biochim Biophys Acta. 1988 Aug 3;948(1):67–85. doi: 10.1016/0304-419x(88)90005-4. [DOI] [PubMed] [Google Scholar]
  32. Noonan K. E., Beck C., Holzmayer T. A., Chin J. E., Wunder J. S., Andrulis I. L., Gazdar A. F., Willman C. L., Griffith B., Von Hoff D. D. Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7160–7164. doi: 10.1073/pnas.87.18.7160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Partanen J., Mäkelä T. P., Eerola E., Korhonen J., Hirvonen H., Claesson-Welsh L., Alitalo K. FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. EMBO J. 1991 Jun;10(6):1347–1354. doi: 10.1002/j.1460-2075.1991.tb07654.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Reid H. H., Wilks A. F., Bernard O. Two forms of the basic fibroblast growth factor receptor-like mRNA are expressed in the developing mouse brain. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1596–1600. doi: 10.1073/pnas.87.4.1596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rifkin D. B., Moscatelli D. Recent developments in the cell biology of basic fibroblast growth factor. J Cell Biol. 1989 Jul;109(1):1–6. doi: 10.1083/jcb.109.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rubin J. S., Osada H., Finch P. W., Taylor W. G., Rudikoff S., Aaronson S. A. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A. 1989 Feb;86(3):802–806. doi: 10.1073/pnas.86.3.802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ruoslahti E., Yamaguchi Y. Proteoglycans as modulators of growth factor activities. Cell. 1991 Mar 8;64(5):867–869. doi: 10.1016/0092-8674(91)90308-l. [DOI] [PubMed] [Google Scholar]
  38. Ruta M., Burgess W., Givol D., Epstein J., Neiger N., Kaplow J., Crumley G., Dionne C., Jaye M., Schlessinger J. Receptor for acidic fibroblast growth factor is related to the tyrosine kinase encoded by the fms-like gene (FLG). Proc Natl Acad Sci U S A. 1989 Nov;86(22):8722–8726. doi: 10.1073/pnas.86.22.8722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Safran A., Avivi A., Orr-Urtereger A., Neufeld G., Lonai P., Givol D., Yarden Y. The murine flg gene encodes a receptor for fibroblast growth factor. Oncogene. 1990 May;5(5):635–643. [PubMed] [Google Scholar]
  40. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  41. Saksela O., Moscatelli D., Sommer A., Rifkin D. B. Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation. J Cell Biol. 1988 Aug;107(2):743–751. doi: 10.1083/jcb.107.2.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sato Y., Rifkin D. B. Autocrine activities of basic fibroblast growth factor: regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis. J Cell Biol. 1988 Sep;107(3):1199–1205. doi: 10.1083/jcb.107.3.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schulze-Osthoff K., Risau W., Vollmer E., Sorg C. In situ detection of basic fibroblast growth factor by highly specific antibodies. Am J Pathol. 1990 Jul;137(1):85–92. [PMC free article] [PubMed] [Google Scholar]
  44. Stampfer M. R., Bartley J. C. Induction of transformation and continuous cell lines from normal human mammary epithelial cells after exposure to benzo[a]pyrene. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2394–2398. doi: 10.1073/pnas.82.8.2394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Taira M., Yoshida T., Miyagawa K., Sakamoto H., Terada M., Sugimura T. cDNA sequence of human transforming gene hst and identification of the coding sequence required for transforming activity. Proc Natl Acad Sci U S A. 1987 May;84(9):2980–2984. doi: 10.1073/pnas.84.9.2980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Takahashi J. A., Mori H., Fukumoto M., Igarashi K., Jaye M., Oda Y., Kikuchi H., Hatanaka M. Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5710–5714. doi: 10.1073/pnas.87.15.5710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Takahashi K., Suzuki K., Kawahara S., Ono T. Growth stimulation of human breast epithelial cells by basic fibroblast growth factor in serum-free medium. Int J Cancer. 1989 May 15;43(5):870–874. doi: 10.1002/ijc.2910430522. [DOI] [PubMed] [Google Scholar]
  48. Theillet C., Le Roy X., De Lapeyrière O., Grosgeorges J., Adnane J., Raynaud S. D., Simony-Lafontaine J., Goldfarb M., Escot C., Birnbaum D. Amplification of FGF-related genes in human tumors: possible involvement of HST in breast carcinomas. Oncogene. 1989 Jul;4(7):915–922. [PubMed] [Google Scholar]
  49. Valverius E. M., Ciardiello F., Heldin N. E., Blondel B., Merlo G., Smith G., Stampfer M. R., Lippman M. E., Dickson R. B., Salomon D. S. Stromal influences on transformation of human mammary epithelial cells overexpressing c-myc and SV40T. J Cell Physiol. 1990 Nov;145(2):207–216. doi: 10.1002/jcp.1041450204. [DOI] [PubMed] [Google Scholar]
  50. Wang A. M., Doyle M. V., Mark D. F. Quantitation of mRNA by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9717–9721. doi: 10.1073/pnas.86.24.9717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Yayon A., Klagsbrun M., Esko J. D., Leder P., Ornitz D. M. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell. 1991 Feb 22;64(4):841–848. doi: 10.1016/0092-8674(91)90512-w. [DOI] [PubMed] [Google Scholar]
  52. Zhan X., Bates B., Hu X. G., Goldfarb M. The human FGF-5 oncogene encodes a novel protein related to fibroblast growth factors. Mol Cell Biol. 1988 Aug;8(8):3487–3495. doi: 10.1128/mcb.8.8.3487. [DOI] [PMC free article] [PubMed] [Google Scholar]

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