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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

Activation state of the AR pathway in the PC346DCC, PC346Flu1 and PC346Flu2.Differentially-expressed genes in PC346 hormone-refractory sublines versus parental PC346C were linked to a previously established androgen-response gene signature (see Materials and Methods section). (A) Heat-map representation of androgen-responsive genes deregulated in any of the PC346 hormone-refractory sublines. Color scheme as described in Fig. 1. (B) Venn-diagram and respective statistics.
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pone-0013500-g002: Activation state of the AR pathway in the PC346DCC, PC346Flu1 and PC346Flu2.Differentially-expressed genes in PC346 hormone-refractory sublines versus parental PC346C were linked to a previously established androgen-response gene signature (see Materials and Methods section). (A) Heat-map representation of androgen-responsive genes deregulated in any of the PC346 hormone-refractory sublines. Color scheme as described in Fig. 1. (B) Venn-diagram and respective statistics.

Mentions: To investigate the activation state of the AR pathway in the PC346DCC, PC346Flu1 and PC346Flu2, the SRS database was used to link and compare our present data with a previously established androgen-response gene signature (Fig. 2A). This androgen-response signature was determined by expression microarray analysis, after stimulation of the different PC346 cell lines with the synthetic androgen R1881 or the antiandrogen hydroxyflutamide (Table S4). Of the 487 differentially-regulated transcripts in the therapy-resistant sublines, only 27 were AR target genes (<6%), indicating that other genes and pathways are also involved in hormone-therapy refractory proliferation of these sublines. Furthermore, AR target genes were down-regulated in PC346DCC (p-value  = 10−7), whereas their expression in PC346Flu1 and PC346Flu2 was not significantly affected (Fig. 2B). However, although not statistically significant for the AR pathway as a whole, PC346Flu1 and PC346Flu2 did show lower induction of some androgen-responsive genes such as KLK2, STEAP1, STEAP2 and EHF.


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)

Activation state of the AR pathway in the PC346DCC, PC346Flu1 and PC346Flu2.Differentially-expressed genes in PC346 hormone-refractory sublines versus parental PC346C were linked to a previously established androgen-response gene signature (see Materials and Methods section). (A) Heat-map representation of androgen-responsive genes deregulated in any of the PC346 hormone-refractory sublines. Color scheme as described in Fig. 1. (B) Venn-diagram and respective statistics.
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Related In: Results  -  Collection

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

pone-0013500-g002: Activation state of the AR pathway in the PC346DCC, PC346Flu1 and PC346Flu2.Differentially-expressed genes in PC346 hormone-refractory sublines versus parental PC346C were linked to a previously established androgen-response gene signature (see Materials and Methods section). (A) Heat-map representation of androgen-responsive genes deregulated in any of the PC346 hormone-refractory sublines. Color scheme as described in Fig. 1. (B) Venn-diagram and respective statistics.
Mentions: To investigate the activation state of the AR pathway in the PC346DCC, PC346Flu1 and PC346Flu2, the SRS database was used to link and compare our present data with a previously established androgen-response gene signature (Fig. 2A). This androgen-response signature was determined by expression microarray analysis, after stimulation of the different PC346 cell lines with the synthetic androgen R1881 or the antiandrogen hydroxyflutamide (Table S4). Of the 487 differentially-regulated transcripts in the therapy-resistant sublines, only 27 were AR target genes (<6%), indicating that other genes and pathways are also involved in hormone-therapy refractory proliferation of these sublines. Furthermore, AR target genes were down-regulated in PC346DCC (p-value  = 10−7), whereas their expression in PC346Flu1 and PC346Flu2 was not significantly affected (Fig. 2B). However, although not statistically significant for the AR pathway as a whole, PC346Flu1 and PC346Flu2 did show lower induction of some androgen-responsive genes such as KLK2, STEAP1, STEAP2 and EHF.

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