Mp68-20 Establishing a Negative Feedback Loop Between Fibroblast Growth Factor 5 and Androgen Receptor in Prostate Cancer
Year: 2019
Type: article
Abstract: You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II (MP68)1 Apr 2019MP68-20 ESTABLISHING A NEGATIVE FEEDBACK LOOP BETWEEN FIBROBLAST GROWTH FACTOR 5 AND ANDROGEN RECEPTOR IN PROSTATE CANCER Dalton McLean*, Katelin Cunningham, and William Ricke Dalton McLean*Dalton McLean* More articles by this author , Katelin CunninghamKatelin Cunningham More articles by this author , and William RickeWilliam Ricke More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000557035.55627.d7AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Prostate cancer (PRCA) is the 3rd most prevalent type of cancer behind breast and lung cancer, with >220,000 new cases arising per year in the United States. The 5-year survival rate for prostate cancer is >98%, but patients that have undergone androgen deprivation therapy (ADT) to treat advanced prostate cancer will develop castration resistant prostate cancer (CRPC) in 10-20% of cases, with survival rates dropping to 29%. The purpose of this study was to investigate the role of increasing FGF5 expression in the progression of PRCA. METHODS: Utilizing the LNCaP series and the BCaP cell line model of prostate cancer progression, we assessed FGF5 expression and function in vitro. Overexpression plasmids and recombinant FGF5 (rFGF5) were used for gain of function (GOF) studies, while siRNA was used for loss of function. We used a progression tissue microarray (pTMA) to assess FGF5 expression in a clinical context (n=384). RESULTS: GOF experiments revealed that FGF5 significantly increases the expression of androgen receptor (AR) mRNA and protein. In addition, FGF5 was found to induce nuclear localization and activation of AR in the absence of ligand, suggesting ligand-independent activation of AR by FGF5. Conversely, when FGF5 was inhibited using siRNA in a cell line expressing high levels of AR mRNA and FGF5, AR mRNA was significantly decreased. When androgen-dependent LNCaP cells were subjected to an androgen-depleted environment, to mimic ADT, FGF5 protein and mRNA significantly increased. Additionally, when AR was stimulated using androgen, FGF5 protein and mRNA levels significantly decreased. These effects are not observed in cell lines that do not express AR or are AR-independent suggesting AR is directly regulating FGF5. Finally, in the BCaP model there was a significant increase in the mRNA and protein expression of FGF5 in tumorigenic cell lines compared to nontumorigenic. TMA analysis of clinical samples revealed a significant increase in FGF5-positive cells across progression of prostate cancer from benign to metastatic. CONCLUSIONS: To our knowledge, this is the first characterization of the expression and role of FGF5 in the prostate. Our results suggest that the increase in FGF5 expression in PRCA progression could lead to an increase in AR over time, and that this increase in FGF5 could be induced in men on ADT. The mechanism of how FGF5 increases AR will be investigated next, as this could be implicated in the emergence of CRPC following ADT. Source of Funding: 1U54DK104310-01 T32 CA009135 Madison, WI© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e983-e983 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Dalton McLean* More articles by this author Katelin Cunningham More articles by this author William Ricke More articles by this author Expand All Advertisement PDF downloadLoading ...
Source: The Journal of Urology
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2941424251