MP84-05 THE OESTROGEN RECEPTOR IS SIGNIFICANTLY DYSREGULATED IN A MODEL OF DOCETAXEL RESISTANT PROSTATE CANCER AND TAMOXIFEN REVERSES APOPTOTIC RESISTANCE TO DOCETAXEL IN VITRO.

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2016MP84-05 THE OESTROGEN RECEPTOR IS SIGNIFICANTLY DYSREGULATED IN A MODEL OF DOCETAXEL RESISTANT PROSTATE CANCER AND TAMOXIFEN REVERSES APOPTOTIC RESISTANCE TO DOCETAXEL IN VITRO. Dara Lundon, Maria Prencipe, Amanda O'Neill, Sinead Ahearne, Stephen Madden, Padraig Doolan, and William Watson Dara LundonDara Lundon More articles by this author , Maria PrencipeMaria Prencipe More articles by this author , Amanda O'NeillAmanda O'Neill More articles by this author , Sinead AhearneSinead Ahearne More articles by this author , Stephen MaddenStephen Madden More articles by this author , Padraig DoolanPadraig Doolan More articles by this author , and William WatsonWilliam Watson More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2229AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The armamentarium of agents for the treatment of advanced prostate cancer has been significantly augmented in recent years. However the optimal treatment pathway for each man is still poorly defined. Docetaxel is an important chemotherapeutic drug in the treatment of prostate cancer, being amongst the most effective chemotherapeutic agents for the treatment of metastatic castrate-resistant prostate cancer. Docetaxel-resistance is a major obstacle in such patients. Defining the mechanisms underlying resistance so as to inform treatment selection remains a challenge. Previous experiments and publications in our laboratory have shown complex changes in pro and anti-apoptotic proteins in the development of docetaxel resistance. When targeted individually these proteins do not significantly impact upon the resistant phenotype. Our hypothesis was that targeting the central signalling pathways and transcription factors (TF) which control these could represent a more appropriate mechanism for identifying potential therapeutic targets and prognostic markers. Our aims were to identify potential targets/markers and then to undertake a validation of their functional role in a model of docetaxel resistance. METHODS We have developed a number of doxetaxel resistant sublines in PC-3 cells, and undertaken a transciptomic analysis of these cells by DNA microarray analysis using the Affymetrix Human Gene 1.0 ST Array. Using novel bioinformatic techniques, including correspondence, between-group and co-inertia analyses; transcriptional targets suitable for discerning patients with a phenotype of Docetaxel-resistance were identified. Manipulation with tamoxifen and estradiol, was used to determine functional effects on the apoptotic pathway by propidium iodide DNA staining and flow cytometry. RESULTS The TF ESR1, also known as the oestrogen receptor is amongst those predicted to be responsible for the differential gene expression observed in docetaxel-resistant prostate cancer. We have mapped the cell-processes of this TF and can display how it is intimately implicated in regulating docetaxel resistance in prostate cancer cell lines. We have demonstrated the close interplay of ESR1 on apoptosis, response to stress, chemotaxis and chemosensitivity amongst a myriad of inveigling functions. Manipulation of ESR1 in the PC3 docetaxel-resistant cells resulted in altered apoptotic resistance to docetaxel; whereby tamoxifen in combination with docetaxel resulted in a significant increase in apoptosis (p<0.01), and estradiol attenuated resistance (p<0.05) in this cell line model of advanced prostate cancer. CONCLUSIONS Due to the complexity of changes associated with the development of resistance to docetaxel, manipulating the upstream transcription factors and their networks may represent a more comprehensive therapeutic targeting approach for this advanced form of prostate cancer. We have successfully identified ESR1 as being dysregulated in a model of advanced prostate cancer and commenced validation of its functional role in docetaxel resistance in-vitro. The identification of TFs such as ESR1 could be utilised to help stratify men with prostate cancer, as potential therapeutic targets, prognostic aides and predictors of response to docetaxel or combined therapy in men with significant prostate cancer. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1091 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Dara Lundon More articles by this author Maria Prencipe More articles by this author Amanda O'Neill More articles by this author Sinead Ahearne More articles by this author Stephen Madden More articles by this author Padraig Doolan More articles by this author William Watson More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...