title: Role and expression of FRS2 and FRS3 in prostate cancer.
abstract: BACKGROUND
  FGF receptor substrates (FRS2 and FRS3) are key adaptor proteins that mediate FGF-FGFR signalling in benign as well as malignant tissue. Here we investigated FRS2 and FRS3 as a means of disrupting global FGF signalling in prostate cancer.
  
  
  METHODS
  FRS2 and FRS3 manipulation was investigated in vitro using over-expression, knockdown and functional assays. FRS2 and FRS3 expression was profiled in cell lines and clinical tumors of different grades.
  
  
  RESULTS
  In a panel of cell lines we observed ubiquitous FRS2 and FRS3 transcript and protein expression in both benign and malignant cells. We next tested functional redundancy of FRS2 and FRS3 in prostate cancer cells. In DU145 cells, specific FRS2 suppression inhibited FGF induced signalling. This effect was not apparent in cells stably over-expressing FRS3. Indeed FRS3 over-expression resulted in enhanced proliferation (p = 0.005) compared to control cells. Given this functional redundancy, we tested the therapeutic principle of dual targeting of FRS2 and FRS3 in prostate cancer. Co-suppression of FRS2 and FRS3 significantly inhibited ERK activation with a concomitant reduction in cell proliferation (p < 0.05), migration and invasion (p < 0.05). Synchronous knockdown of FRS2 and FRS3 with exposure to cytotoxic irradiation resulted in a significant reduction in prostate cancer cell survival compared to irradiation alone (p < 0.05). Importantly, this synergistic effect was not observed in benign cells. Finally, we investigated expression of FRS2 and FRS3 transcript in a cohort of micro-dissected tumors of different grades as well as by immunohistochemistry in clinical biopsies. Here, we did not observe any difference in expression between benign and malignant biopsies.
  
  
  CONCLUSIONS
  These results suggest functional overlap of FRS2 and FRS3 in mediating mitogenic FGF signalling in the prostate. FRS2 and FRS3 are not over-expressed in tumours but targeted dual inhibition may selectively adversely affect malignant but not benign prostate cells.
authors.affiliation: Translational Prostate Cancer Group, Department of Oncology, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK.
authors.forename: Tania
authors.initials: T
authors.lastname: Valencia
authors.forename: Ajay
authors.initials: A
authors.lastname: Joseph
authors.forename: Naveen
authors.initials: N
authors.lastname: Kachroo
authors.forename: Steve
authors.initials: S
authors.lastname: Darby
authors.forename: Susan
authors.initials: S
authors.lastname: Meakin
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Gnanapragasam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000528:radiation effects; D015331:Cohort Studies; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C106534:FRS2 protein, human; C113566:FRS3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins
references.citation: Cell Res. 2009 Oct;19(10):1165-77
references.pmid: 19652666
references.citation: Prostate. 2002 Aug 1;52(3):245-52
references.pmid: 12111699
references.citation: Cancer Cell. 2010 Jul 13;18(1):11-22
references.pmid: 20579941
references.citation: Oncogene. 2010 May 27;29(21):3087-99
references.pmid: 20228838
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8578-83
references.pmid: 11447289
references.citation: J Pathol. 2007 Sep;213(1):82-90
references.pmid: 17607666
references.citation: In Vitro Cell Dev Biol Anim. 2002 Mar;38(3):178-83
references.pmid: 12026167
references.citation: J Biol Chem. 1998 Jul 17;273(29):17987-90
references.pmid: 9660748
references.citation: Br J Cancer. 2003 May 6;88(9):1432-8
references.pmid: 12778074
references.citation: J Neurochem. 2010 Feb;112(4):924-39
references.pmid: 19943849
references.citation: J Clin Invest. 2008 Aug;118(8):2697-710
references.pmid: 18618013
references.citation: Oncogene. 2006 Oct 19;25(49):6457-66
references.pmid: 16702953
references.citation: Mol Cell Biol. 2001 Jul;21(13):4177-87
references.pmid: 11390647
references.citation: Biochim Biophys Acta. 2006 Apr;1763(4):366-80
references.pmid: 16697063
references.citation: Int J Radiat Biol. 2001 Oct;77(10):1067-78
references.pmid: 11682011
references.citation: Int J Oncol. 2006 Aug;29(2):407-12
references.pmid: 16820883
references.citation: Cell. 1997 May 30;89(5):693-702
references.pmid: 9182757
references.citation: FASEB J. 2002 Aug;16(10):1283-5
references.pmid: 12154000
references.citation: J Pathol. 2004 Dec;204(5):578-86
references.pmid: 15538740
references.citation: Int J Cancer. 1999 Jul 19;82(2):237-43
references.pmid: 10389758
references.citation: J Biol Chem. 1999 Apr 2;274(14):9861-70
references.pmid: 10092678
references.citation: Oncogene. 1998 May 28;16(21):2787-96
references.pmid: 9652746
references.citation: Cancer Res. 1997 Dec 1;57(23):5369-78
references.pmid: 9393762
references.citation: J Pathol. 2010 Mar;220(4):452-60
references.pmid: 19960500
references.citation: Radiat Res. 2003 Apr;159(4):439-52
references.pmid: 12643788
references.citation: Mol Biol Cell. 1999 Aug;10(8):2493-506
references.pmid: 10436007
references.citation: Methods Mol Biol. 2011;755:291-300
references.pmid: 21761313
references.citation: FEBS Lett. 2004 Apr 23;564(1-2):14-8
references.pmid: 15094036
references.citation: Pharmacol Ther. 2010 Jan;125(1):105-17
references.pmid: 19874848
references.citation: Cancer Res. 2003 Oct 1;63(19):6237-43
references.pmid: 14559809
references.citation: Mol Cancer Ther. 2003 Nov;2(11):1113-20
references.pmid: 14617784
references.citation: Nat Rev Cancer. 2010 Feb;10(2):116-29
references.pmid: 20094046
references.citation: Lab Invest. 2001 Jun;81(6):815-26
references.pmid: 11406643
references.citation: Endocrinology. 2003 Mar;144(3):922-8
references.pmid: 12586769
references.citation: Oncogene. 1999 Apr 29;18(17):2755-61
references.pmid: 10348350
references.citation: Endocr Relat Cancer. 2004 Dec;11(4):709-24
references.pmid: 15613447
references.citation: Mol Cell Biol. 2005 May;25(10):4105-16
references.pmid: 15870281
references.citation: J Natl Cancer Inst. 2001 Dec 5;93(23):1783-90
references.pmid: 11734594
references.citation: Oncogene. 1999 Aug 19;18(33):4756-66
references.pmid: 10467423
references.citation: Int J Cancer. 2010 Dec 1;127(11):2491-9
references.pmid: 20607827