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Updated: Jun 17, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
14-3-3{eta} Amplifies Androgen Receptor Actions in Prostate Cancer
Mark A Titus1, Jiann-An Tan, Christopher W Gregory
1Authors' Affiliations: Departments of Pediatrics (Laboratories for Reproductive Biology), Surgery (Division of Urology) and Pathology and Laboratory Medicine, Biochemistry and Biophysics, and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina; Department of Urologic Oncology, Roswell Park Cancer Institute, and Department of Urology, University at Buffalo School of Medicine and Biotechnology, Buffalo, New York; and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia.
Abstract:
PURPOSE: Androgen receptor abundance and androgen receptor-regulated gene expression in castration-recurrent prostate cancer are indicative of androgen receptor activation in the absence of testicular androgen. Androgen receptor transactivation of target genes in castration-recurrent prostate cancer occurs in part through mitogen signaling that amplifies the actions of androgen receptor and its coregulators. Herein we report on the role of 14-3-3eta in androgen receptor action. Experimental Design and RESULTS: Androgen receptor and 14-3-3eta colocalized in COS cell nuclei with and without androgen, and 14-3-3eta promoted androgen receptor nuclear localization in the absence of androgen. 14-3-3eta interacted with androgen receptor in cell-free binding and coimmunoprecipitation assays. In the recurrent human prostate cancer cell line, CWR-R1, native endogenous androgen receptor transcriptional activation was stimulated by 14-3-3eta at low dihydrotestosterone concentrations and was increased by epidermal growth factor. Moreover, the dihydrotestosterone- and epidermal growth factor-dependent increase in androgen receptor transactivation was inhibited by a dominant negative 14-3-3eta. In the CWR22 prostate cancer xenograft model, 14-3-3eta expression was increased by androgen, suggesting a feed-forward mechanism that potentiates both 14-3-3eta and androgen receptor actions. 14-3-3eta mRNA and protein decreased following castration of tumor-bearing mice and increased in tumors of castrate mice after treatment with testosterone. CWR22 tumors that recurred 5 months after castration contained 14-3-3eta levels similar to the androgen-stimulated tumors removed before castration. In a human prostate tissue microarray of clinical specimens, 14-3-3eta localized with androgen receptor in nuclei, and the similar amounts expressed in castration-recurrent prostate cancer, androgen-stimulated prostate cancer, and benign prostatic hyperplasia were consistent with androgen receptor activation in recurrent prostate cancer. CONCLUSION: 14-3-3eta enhances androgen- and mitogen-induced androgen receptor transcriptional activity in castration-recurrent prostate cancer. (Clin Cancer Res 2009;15(24):7571-81).
Insights
14-3-3eta protein enhances androgen receptor activity in recurrent prostate cancer. This protein promotes androgen receptor nuclear localization and transcriptional activity, even without testosterone, suggesting a key role in castration-resistant prostate cancer progression.
Area of Science:
- Molecular Biology
- Oncology
- Endocrinology
Background:
- Androgen receptor (AR) activation drives prostate cancer growth, even in castration-recurrent settings.
- Mitogen signaling pathways can amplify AR actions in prostate cancer.
- The role of 14-3-3eta in AR signaling within prostate cancer is not fully understood.
Purpose of the Study:
- To investigate the role of 14-3-3eta in androgen receptor (AR) action in castration-recurrent prostate cancer.
- To determine if 14-3-3eta influences AR nuclear localization and transcriptional activity.
- To examine the expression and regulation of 14-3-3eta in prostate cancer models and clinical specimens.
Main Methods:
- Co-localization studies of AR and 14-3-3eta in COS cells.
- Binding assays (cell-free and co-immunoprecipitation) to assess AR-14-3-3eta interaction.
- Functional assays in CWR-R1 prostate cancer cells and CWR22 xenografts to evaluate AR transcriptional activity.
- Analysis of 14-3-3eta expression in response to androgen manipulation and in human prostate cancer tissues.
Main Results:
- 14-3-3eta promoted AR nuclear localization in the absence of androgen and interacted with AR.
- 14-3-3eta stimulated AR transcriptional activity at low dihydrotestosterone (DHT) concentrations, enhanced by epidermal growth factor (EGF).
- 14-3-3eta expression increased with androgen stimulation in CWR22 xenografts and was elevated in recurrent tumors.
- Human prostate cancer tissues showed nuclear co-localization of 14-3-3eta and AR, with similar expression levels across different stages.
Conclusions:
- 14-3-3eta enhances both androgen- and mitogen-induced AR transcriptional activity in castration-recurrent prostate cancer.
- 14-3-3eta may play a significant role in promoting AR signaling and driving prostate cancer progression after castration.
- The findings suggest 14-3-3eta as a potential therapeutic target in advanced prostate cancer.
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