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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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Expression of the androgen-independent PC346DCC signature genes in prostate cancer samples from patient tumors.The 276-gene signature from PC346DCC was linked to data from 7 prostate cancer microarray databases of primary (Lapointe, Varambally, Tomlins, Yu), metastatic (Chandran, Lapointe, Varambally, Tomlins, Yu) and hormone-therapy refractory tumors (Tamura, Tomlins and Best). Only genes present in at least 5/7 databases (209 genes) and deregulated in at least 3/7 (111 genes) were included in the analysis. Heat-map representation of (A) 72 overexpressed and (B) 39 repressed genes in PC346DCC. (C) Deregulated genes selected for further qPCR analysis. Color scheme as described in Fig. 1. Grey squares indicate missing data, either due to low expression levels, poor data quality or absence of probes for the respective transcript in the array platform used for the study. PC-NAP: prostate cancer minus normal adjacent prostate; MET-PC: metastasis minus primary prostate tumors; HR-HN: hormone-therapy refractory minus hormone-naïve tumors.
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pone-0013500-g004: Expression of the androgen-independent PC346DCC signature genes in prostate cancer samples from patient tumors.The 276-gene signature from PC346DCC was linked to data from 7 prostate cancer microarray databases of primary (Lapointe, Varambally, Tomlins, Yu), metastatic (Chandran, Lapointe, Varambally, Tomlins, Yu) and hormone-therapy refractory tumors (Tamura, Tomlins and Best). Only genes present in at least 5/7 databases (209 genes) and deregulated in at least 3/7 (111 genes) were included in the analysis. Heat-map representation of (A) 72 overexpressed and (B) 39 repressed genes in PC346DCC. (C) Deregulated genes selected for further qPCR analysis. Color scheme as described in Fig. 1. Grey squares indicate missing data, either due to low expression levels, poor data quality or absence of probes for the respective transcript in the array platform used for the study. PC-NAP: prostate cancer minus normal adjacent prostate; MET-PC: metastasis minus primary prostate tumors; HR-HN: hormone-therapy refractory minus hormone-naïve tumors.

Mentions: To identify genes modulated in PCa that could explain hormone-therapy refractory growth through bypass of the AR pathway, we linked the 276-gene signature from PC346DCC with data from seven PCa microarray studies published previously (Table 5) [14], [29], [30], [31], [32], [33], [34]. Only genes present in at least 5/7 databases (209 genes) and deregulated in at least 3/7 (111 genes) were included for further analysis. Hierarchical clustering performed on the signature genes (first column), next to primary cancer vs. normal prostate (second column), metastatic cancer vs. primary cancer (third column), and finally hormone-refractory vs. hormone-naïve disease (fourth column), is shown in Fig. 4. Approximately 30% of the genes differentially expressed in PC346DCC were found to be consistently deregulated in metastatic PCa compared to organ-confined disease.


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)

Expression of the androgen-independent PC346DCC signature genes in prostate cancer samples from patient tumors.The 276-gene signature from PC346DCC was linked to data from 7 prostate cancer microarray databases of primary (Lapointe, Varambally, Tomlins, Yu), metastatic (Chandran, Lapointe, Varambally, Tomlins, Yu) and hormone-therapy refractory tumors (Tamura, Tomlins and Best). Only genes present in at least 5/7 databases (209 genes) and deregulated in at least 3/7 (111 genes) were included in the analysis. Heat-map representation of (A) 72 overexpressed and (B) 39 repressed genes in PC346DCC. (C) Deregulated genes selected for further qPCR analysis. Color scheme as described in Fig. 1. Grey squares indicate missing data, either due to low expression levels, poor data quality or absence of probes for the respective transcript in the array platform used for the study. PC-NAP: prostate cancer minus normal adjacent prostate; MET-PC: metastasis minus primary prostate tumors; HR-HN: hormone-therapy refractory minus hormone-naïve tumors.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2957443&req=5

pone-0013500-g004: Expression of the androgen-independent PC346DCC signature genes in prostate cancer samples from patient tumors.The 276-gene signature from PC346DCC was linked to data from 7 prostate cancer microarray databases of primary (Lapointe, Varambally, Tomlins, Yu), metastatic (Chandran, Lapointe, Varambally, Tomlins, Yu) and hormone-therapy refractory tumors (Tamura, Tomlins and Best). Only genes present in at least 5/7 databases (209 genes) and deregulated in at least 3/7 (111 genes) were included in the analysis. Heat-map representation of (A) 72 overexpressed and (B) 39 repressed genes in PC346DCC. (C) Deregulated genes selected for further qPCR analysis. Color scheme as described in Fig. 1. Grey squares indicate missing data, either due to low expression levels, poor data quality or absence of probes for the respective transcript in the array platform used for the study. PC-NAP: prostate cancer minus normal adjacent prostate; MET-PC: metastasis minus primary prostate tumors; HR-HN: hormone-therapy refractory minus hormone-naïve tumors.
Mentions: To identify genes modulated in PCa that could explain hormone-therapy refractory growth through bypass of the AR pathway, we linked the 276-gene signature from PC346DCC with data from seven PCa microarray studies published previously (Table 5) [14], [29], [30], [31], [32], [33], [34]. Only genes present in at least 5/7 databases (209 genes) and deregulated in at least 3/7 (111 genes) were included for further analysis. Hierarchical clustering performed on the signature genes (first column), next to primary cancer vs. normal prostate (second column), metastatic cancer vs. primary cancer (third column), and finally hormone-refractory vs. hormone-naïve disease (fourth column), is shown in Fig. 4. Approximately 30% of the genes differentially expressed in PC346DCC were found to be consistently deregulated in metastatic PCa compared to organ-confined disease.

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