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Updated: Aug 5, 2026
Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer
Published on: November 2, 2013
Microarray analysis of prostate cancer progression to reduced androgen dependence: studies in unique models contrasts
F M Sirotnak1, Yuhong She, Nushmia Z Khokhar
1Department of Medicine, Program of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Abstract:
Three unique variants of the CWR22 human prostate cancer xenograft model (CWR22LD1, LD2, and LD3) with a decrease in dependence on androgens were selected under noncastrate conditions, i.e., by outgrowth after transplantation into male NCR (AT) nu mice without testosterone supplementation. These variants were unable to grow in castrated male mice. For comparison, a second set of variants with even less dependence on androgens (castrate-resistant) were derived following outgrowth from CWR22 (CWR22Rv1 and RC) or CWRLD1 (CWR22RS) after transplantion in castrated male mice. The androgen receptor (AR) gene in the CWR22LD variants was transcriptionally active and was neither mutated nor significantly overexpressed compared to CWR22. Oligonucleotide microarray analysis showed distinctly different profiles of dysregulated gene expression among the CWR22LD variants. Groups of only 26-41 genes were dysregulated greater than threefold with a different proportion of up versus downregulated genes in each variant. Only one of the castrate-resistant variants (CWR22Rv1) had a highly overexpressed AR gene but AR in this variant and the two other castrate-resistant variants, CWR22 RS and RC, was not mutated beyond that seen in CWR22. In contrast to the CWR22LD variants, a total of 342, 295, and 222 genes were dysregulated at least threefold in CWR22Rv1, CWR22RS, and CWR22RC, respectively, differing as well in the proportion of up versus downregulated genes. Many of the genes dysregulated in CWR22LD1, LD2, and LD3 were further dysregulated in CWR22Rv1, RC, or RS. The most downregulated gene was microseminoprotein beta (MSPB). Along with cyclin D1, the most upregulated gene by an order of magnitude compared to other upregulated genes was hepatocyte growth factor (HGF) (scatter factor). These results suggest that the onset in the loss of androgen dependence in CWR22 proceeds through multiple pathways and does not require any direct change in the status of AR. However, upregulation of other survival pathways like that involving HGF in these studies could co-activate AR signaling. The endogenous overexpression of genes regulating sterol biosynthesis also observed in castrate-resistant CWR22 variants delineated a clinically relevant, compensatory mechanism for overcoming androgen deprivation reaffirming a central role for AR signaling in this process.
Insights
Prostate cancer cells can lose androgen dependence through multiple pathways without direct androgen receptor (AR) gene changes. Upregulation of survival pathways like hepatocyte growth factor (HGF) may co-activate AR signaling.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The CWR22 human prostate cancer xenograft model exhibits androgen dependence.
- Understanding mechanisms of androgen independence is crucial for treating advanced prostate cancer.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the loss of androgen dependence in prostate cancer xenografts.
- To compare gene expression profiles of androgen-dependent and castrate-resistant variants.
Main Methods:
- Selection of androgen-dependent (CWR22LD) and castrate-resistant (CWR22Rv1, RC, RS) variants from CWR22 xenografts.
- Oligonucleotide microarray analysis to assess gene expression dysregulation.
- Analysis of androgen receptor (AR) gene status (mutation, expression).
Main Results:
- CWR22LD variants showed minimal AR gene alterations but distinct gene expression profiles.
- Castrate-resistant variants displayed significant gene dysregulation, with one (CWR22Rv1) showing AR overexpression.
- Hepatocyte growth factor (HGF) and microseminoprotein beta (MSPB) were significantly upregulated and downregulated, respectively.
- Overexpression of sterol biosynthesis genes was observed in castrate-resistant variants.
Conclusions:
- Loss of androgen dependence in CWR22 xenografts occurs via multiple pathways, not solely through AR gene mutations or significant overexpression.
- Upregulation of alternative survival pathways, such as HGF signaling, can contribute to AR signaling co-activation.
- Compensatory mechanisms, including altered sterol biosynthesis, play a role in overcoming androgen deprivation in castrate-resistant prostate cancer.
