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Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.

Marques RB, Dits NF, Erkens-Schulze S, van Weerden WM, Jenster G - PLoS ONE (2010)

Bottom Line: PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10(-7)).Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms.Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands.

ABSTRACT

Background: Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2.

Methodology/principal findings: Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10(-7)). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression.

Conclusions/significance: Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets.

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Related in: MedlinePlus

Biological processes deregulated in the hormone-refractory sublines.Top 5 biological functions enriched in the therapy-resistant sublines: (A) diseases and disorders, (B) molecular and cellular functions. (C) Example of Network analysis for PC346DCC showing deregulation of hormone and growth-factor receptor signaling: up-regulated genes are represented in red and repressed genes in green. Analysis was performed using Ingenuity Pathway Analysis software (www.ingenuity.com).
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pone-0013500-g003: Biological processes deregulated in the hormone-refractory sublines.Top 5 biological functions enriched in the therapy-resistant sublines: (A) diseases and disorders, (B) molecular and cellular functions. (C) Example of Network analysis for PC346DCC showing deregulation of hormone and growth-factor receptor signaling: up-regulated genes are represented in red and repressed genes in green. Analysis was performed using Ingenuity Pathway Analysis software (www.ingenuity.com).

Mentions: The selected 487-gene signature was classified according to Gene Ontology (GO) Biological Processes using the Database for Annotation, Visualization and Integrated Discovery (DAVID) [26], [27]. Annotation clustering analysis showed enrichment in categories involved in organ development, reproductive system differentiation, cellular growth, differentiation and apoptosis (Table 4). Ingenuity Pathway Analysis was used to identify enrichment in “diseases and disorders”, “molecular and cellular functions”, and to search for intrinsic pathways/networks within the selected gene sets (www.ingenuity.com). Cancer and reproductive system disease were ranked in the top 3 of “diseases and disorders”, which logically confirmed the enrichment of genes associated with PCa, such as hepsin, clusterin, vitamin D receptor, trefoil factor 3, tumor protein D52, the AR itself and several of its target genes (Fig. 3A and 3B, respectively). Furthermore, we used Network analysis to screen the 276-gene signature of PC346DCC for potential alternative growth pathways that could be involved in bypassing the AR signaling. Interestingly, signaling via growth-hormone receptor (GHR), insulin receptor (INSR) and epidermal growth factor receptor was among the top 10 Networks (score  = 20) showing deregulation in PC346DCC (Fig. 3C).


Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.

Marques RB, Dits NF, Erkens-Schulze S, van Weerden WM, Jenster G - PLoS ONE (2010)

Biological processes deregulated in the hormone-refractory sublines.Top 5 biological functions enriched in the therapy-resistant sublines: (A) diseases and disorders, (B) molecular and cellular functions. (C) Example of Network analysis for PC346DCC showing deregulation of hormone and growth-factor receptor signaling: up-regulated genes are represented in red and repressed genes in green. Analysis was performed using Ingenuity Pathway Analysis software (www.ingenuity.com).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2957443&req=5

pone-0013500-g003: Biological processes deregulated in the hormone-refractory sublines.Top 5 biological functions enriched in the therapy-resistant sublines: (A) diseases and disorders, (B) molecular and cellular functions. (C) Example of Network analysis for PC346DCC showing deregulation of hormone and growth-factor receptor signaling: up-regulated genes are represented in red and repressed genes in green. Analysis was performed using Ingenuity Pathway Analysis software (www.ingenuity.com).
Mentions: The selected 487-gene signature was classified according to Gene Ontology (GO) Biological Processes using the Database for Annotation, Visualization and Integrated Discovery (DAVID) [26], [27]. Annotation clustering analysis showed enrichment in categories involved in organ development, reproductive system differentiation, cellular growth, differentiation and apoptosis (Table 4). Ingenuity Pathway Analysis was used to identify enrichment in “diseases and disorders”, “molecular and cellular functions”, and to search for intrinsic pathways/networks within the selected gene sets (www.ingenuity.com). Cancer and reproductive system disease were ranked in the top 3 of “diseases and disorders”, which logically confirmed the enrichment of genes associated with PCa, such as hepsin, clusterin, vitamin D receptor, trefoil factor 3, tumor protein D52, the AR itself and several of its target genes (Fig. 3A and 3B, respectively). Furthermore, we used Network analysis to screen the 276-gene signature of PC346DCC for potential alternative growth pathways that could be involved in bypassing the AR signaling. Interestingly, signaling via growth-hormone receptor (GHR), insulin receptor (INSR) and epidermal growth factor receptor was among the top 10 Networks (score  = 20) showing deregulation in PC346DCC (Fig. 3C).

Bottom Line: PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10(-7)).Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms.Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands.

ABSTRACT

Background: Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2.

Methodology/principal findings: Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10(-7)). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression.

Conclusions/significance: Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets.

Show MeSH
Related in: MedlinePlus