title: The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation.
abstract: Docetaxel based therapy is one of the first line chemotherapeutic agents for the treatment of metastatic castrate-resistant prostate cancer. However, one of the major obstacles in the treatment of these patients is docetaxel-resistance. Defining the mechanisms of resistance so as to inform subsequent treatment options and combinations represents a challenge for clinicians and scientists. Previous work by our group has shown complex changes in pro and anti-apoptotic proteins in the development of resistance to docetaxel. Targeting these changes individually does not significantly impact on the resistant phenotype but understanding the central signalling pathways and transcription factors (TFs) which control these could represent a more appropriate therapeutic targeting approach.
  
  
  
  Using a number of docetaxel-resistant sublines of PC-3 cells, we have undertaken a transcriptomic analysis by expression microarray using the Affymetrix Human Gene 1.0 ST Array and in conjunction with bioinformatic analyses undertook to predict dysregulated TFs in docetaxel resistant prostate cancer. The clinical significance of this prediction was ascertained by performing immunohistochemical (IHC) analysis of an identified TF (SRF) in the metastatic sites from men who died of advanced CRPC. Investigation of the functional role of SRF was examined by manipulating SRF using SiRNA in a docetaxel-resistant PC-3 cell line model.
  
  
  
  The transcription factors identified include serum response factor (SRF), nuclear factor kappa-B (NFκB), heat shock factor protein 1 (HSF1), testicular receptor 2 & 4 (TR2 &4), vitamin-D and retinoid x receptor (VDR-RXR) and oestrogen-receptor 1 (ESR1), which are predicted to be responsible for the differential gene expression observed in docetaxel-resistance. IHC analysis to quantify nuclear expression of the identified TF SRF correlates with both survival from date of bone metastasis (p = 0.003), survival from androgen independence (p = 0.00002), and overall survival from prostate cancer (p = 0.0044). Functional knockdown of SRF by siRNA demonstrated a reversal of apoptotic resistance to docetaxel treatment in the docetaxel-resistant PC-3 cell line model.
  
  
  
  Our results suggest that SRF could aid in treatment stratification of prostate cancer, and may also represent a therapeutic target in the treatment of men afflicted with advanced prostate cancer.
authors.affiliation: UCD School of Medicine, Conway Institute of Biomedical and Biomolecular Sciences, University College Dublin, Belfield, Dublin, Dublin 4, Ireland. Dara.Lundon@ucdconnect.ie.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lundon
authors.affiliation: UCD School of Mathematical Sciences and Insight, University College Dublin, Belfield, Dublin, Dublin 4, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Boland
authors.affiliation: UCD School of Medicine, Conway Institute of Biomedical and Biomolecular Sciences, University College Dublin, Belfield, Dublin, Dublin 4, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Prencipe
authors.affiliation: UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Dublin 4, Ireland.
authors.forename: G
authors.initials: G
authors.lastname: Hurley
authors.affiliation: UCD School of Medicine, Conway Institute of Biomedical and Biomolecular Sciences, University College Dublin, Belfield, Dublin, Dublin 4, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: O'Neill
authors.affiliation: Department of Pathology, Beaumont Hospital & Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Kay
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland Non-US/Non-Canadian, Ireland.
authors.forename: S T
authors.initials: ST
authors.lastname: Aherne
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland Non-US/Non-Canadian, Ireland.
authors.forename: P
authors.initials: P
authors.lastname: Doolan
authors.affiliation: UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Dublin 4, Ireland.
authors.forename: S F
authors.initials: SF
authors.lastname: Madden
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland Non-US/Non-Canadian, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Clynes
authors.affiliation: Department of Urology, University of Washington, Seattle, WA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: UCD School of Medicine, Conway Institute of Biomedical and Biomolecular Sciences, University College Dublin, Belfield, Dublin, Dublin 4, Ireland.
authors.forename: J M
authors.initials: JM
authors.lastname: Fitzpatrick
authors.affiliation: UCD School of Medicine, Conway Institute of Biomedical and Biomolecular Sciences, University College Dublin, Belfield, Dublin, Dublin 4, Ireland.
authors.forename: R W
authors.initials: RW
authors.lastname: Watson
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D026362:Serum Response Factor / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D043823:Taxoids / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: C476858:SRF protein, human; D026362:Serum Response Factor; D043823:Taxoids; D014157:Transcription Factors; D000077143:Docetaxel
keywords: Adenocarcinoma of prostate; Androgen-independent prostatic cancer; Anti-neoplastic agent resistance; Docetaxel resistance; Drug resistance; Metastatic prostate cancer; Personalised medicine; Prostate Cancer; Translational oncology