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R William Watson
J M Fitzpatrick
Colm Morrissey
Martin Clynes
Stephen F Madden
Padraig Doolan
Sinead T Aherne
Elaine W Kay
Amanda O'Neill
G Hurley
and 3 others


Medicine & Nursing

androgen independent prostatic cancer anti neoplastic agent resistance translational oncology drug resistance pathology prostate cancer medical pathology personalised medicine adenocarcinoma of prostate docetaxel resistance metastatic prostate cancer

The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation. (2017)

Abstract BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: 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.
Collections Ireland -> Royal College of Surgeons in Ireland -> Pathology Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Pathology

Full list of authors on original publication

R William Watson, J M Fitzpatrick, Colm Morrissey, Martin Clynes, Stephen F Madden, Padraig Doolan, Sinead T Aherne, Elaine W Kay, Amanda O'Neill, G Hurley and 3 others

Experts in our system

R William G Watson
University College Dublin
Total Publications: 134
John M Fitzpatrick
University College Dublin
Total Publications: 129
Martin Clynes
Dublin City University
Total Publications: 209
Stephen F Madden
Dublin City University
Total Publications: 42
Sinéad T Aherne
Dublin City University
Total Publications: 17
Elaine W Kay
Royal College of Surgeons in Ireland
Total Publications: 153
Amanda J O'Neill
University College Dublin
Total Publications: 46