MP33-18 LOSS OF FOXA2 IN NEUROENDOCRINE PROSTATE CANCER LEADS TO INDUCTION OF FUNCTIONAL ANDROGEN RECEPTOR

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP33)1 Sep 2021MP33-18 LOSS OF FOXA2 IN NEUROENDOCRINE PROSTATE CANCER LEADS TO INDUCTION OF FUNCTIONAL ANDROGEN RECEPTOR Zachary M. Connelly, Shu Yang, Siyuan Cheng, and Xiuping Yu Zachary M. ConnellyZachary M. Connelly More articles by this author , Shu YangShu Yang More articles by this author , Siyuan ChengSiyuan Cheng More articles by this author , and Xiuping YuXiuping Yu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002042.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is the leading diagnosed cancer in American men. Current treatments for PCa include surgery, radiation, and hormone therapy. The gold standard in therapeutic interventions for PCa is treatment with anti-androgens; however, PCa can relapse leading to castration-resistant PCa and eventually to neuroendocrine prostate cancer (NEPCa). NEPCa is the most aggressive form of PCa with a life expectancy of less than a year following diagnosis with no available treatment. Hallmarks of NEPCa include loss of the androgen receptor (AR), expression of neuronal markers such as synaptophysin, chromogranin A, and FOXA2, as well as morphological changes resembling a stem-like phenotype. The pioneer transcription factor FOXA2 is expressed embryonically in prostate and is silenced until the NEPCa phenotype occurs. Understanding the roles of FOXA2 is crucial to understanding NEPCa development and progression. METHODS: FOXA2 was stably knocked down in NEPCa PC3 cells (PC3/FOXA2-KD). Additionally, FOXA2 was stably overexpressed in adenocarcinoma (LNCaP). All cells were subjected to RNA and protein analysis. Immunofluorescence was used to visualize AR. Further downstream AR target genes were subjected to mRNA analysis. RESULTS: When FOXA2 was knocked down in PC3 cells, AR increased at both the mRNA transcript and protein levels. Additionally, in LNCaP cells where FOXA2 was overexpressed, AR mRNA and protein levels were decreased. In AR-null PC3 cells where FOXA2 was knocked down, AR localized to the nucleus upon androgen stimulation (Figure 1). Furthermore, upon androgen stimulation, PC3/FOXA2-KD cells stimulated AR target genes including PSA and TMPRSS2. Overall, in AR-null PC3 cells when FOXA2 is knocked down, AR is re-expressed, shows proper nuclear localization, and lastly is functional. CONCLUSIONS: Understanding mechanisms of how PCa progresses into NEPCa and loses the major therapeutic target remains unclear. We provide some of the first evidence where FOXA2 expression inversely correlates with AR expression. By further understanding FOXA2’s role in NEPCa through its regulation of AR expression, previous FOXA2-positive/AR-null NEPCa may be susceptible to anti-androgens again. Source of Funding: FWCC/Foundation Legacy Funds to XY Funding, The Office of Research SEED awards, The Department of Biochemistry & Molecular Biology © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e613-e614 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zachary M. Connelly More articles by this author Shu Yang More articles by this author Siyuan Cheng More articles by this author Xiuping Yu More articles by this author Expand All Advertisement Loading ...