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Updated: Mar 30, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer
Greg L Shaw1, Hayley Whitaker2, Marie Corcoran3
1Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK; University College Hospitals NHS Trust, UK.
Unlabelled:
The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).
Patient Summary:
This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration.
Insights
Castration rapidly alters gene expression in prostate cancer (PCa). Androgen receptor (AR) regulated genes change, and estrogen receptor 1 (ESR1) upregulation may help PCa cells survive treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Androgen receptor (AR) is a key driver of prostate cancer (PCa) growth.
- Understanding AR's regulation of the transcriptome is crucial for PCa treatment.
- Early effects of castration on PCa gene expression were previously uncharacterized.
Purpose of the Study:
- To investigate the rapid changes in gene expression in human prostate cancer following medical castration.
- To identify genes regulated by the androgen receptor (AR) in response to castration.
- To explore the role of estrogen receptor 1 (ESR1) in PCa adaptation to castration.
Main Methods:
- Utilized mass spectrometry, immunohistochemistry, and gene expression arrays.
- Analyzed tumor tissue from 27 patients medically castrated with degarelix prior to prostatectomy.
- Validated findings using reverse transcription-polymerase chain reaction (RT-PCR).
Main Results:
- Observed differential expression of known AR-regulated genes (e.g., TMPRSS2, KLK3).
- Identified 749 downregulated and 908 upregulated genes post-castration.
- Confirmed AR regulation of specific genes and observed ESR1 upregulation associated with proliferation.
Conclusions:
- This study provides the first comprehensive analysis of rapid gene expression changes in PCa after castration.
- AR-regulated gene expression changes are significant and can be predictive of treatment outcomes.
- Upregulation of ESR1 represents a potential survival mechanism for PCa cells under castration pressure.
