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PCR Analysis of Androgen-Regulated Genes in Human Lncap Prostate Cancer Cells

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PCR Analysis of Androgen-Regulated Genes in Human Lncap Prostate Cancer Cells Oncogene (2009) 28, 2051–2063 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ONCOGENOMICS Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells S Ngan, EA Stronach, A Photiou, J Waxman, S Ali and L Buluwela Department of Oncology, Imperial College London, London, UK The androgen receptor (AR) mediates the growth- 2006). The importance of AR in male development is stimulatory effects of androgens in prostate cancer cells. shown by the androgen insensitivity syndromes char- Identification of androgen-regulated genes in prostate acterized by mutations in the AR gene (Gottlieb et al., cancer cells is therefore of considerable importance for 2004). The prostate is a prototypical androgen-depen- defining the mechanisms of prostate-cancer development dent organ (Cunha et al., 1987; Davies and Eaton, 1991) and progression. Although several studies have used and prostate cancer, which has become the most microarrays to identify AR-regulated genes in prostate commonly diagnosed cancer in males in the western cancer cell lines and in prostate tumours, we present here world and is the second leading cause of male cancer the results of gene expression microarray profiling of the death, is androgen-dependent for its growth (Carter and androgen-responsive LNCaP prostate-cancer cell line Coffey, 1990; McConnell, 1991). Therefore, treatment is treated withR1881 for theidentification of androgen- directed at inhibiting prostate cancer growth by regulated genes. We show that the expression of 319 genes suppressing the action of the endogenous androgen or is stimulated by 24 hafter R1881 addition, witha similar its production. Standard treatment involves surgical or number (300) of genes being significantly repressed. pharmacological orchidectomy or inhibition of AR Expression of the upregulated genes, as well as of 60 of activity using anti-androgens that compete with andro- the most robustly downregulated genes, was carried out gen for binding to AR. Following initial response, using quantitative RT–PCR (Q-RT–PCR) over a time- however, almost all tumours eventually progress, as course of R1881 treatment from 0 to 72 h. Q-RT–PCR reflected by the growth of androgen-independent cells was also carried out following treatment withotherAR and the development of hormone-refractory disease. agonists (dihydrotestosterone, estradiol and medroxypro- The continued involvement of the AR in resistant gesterone) and antagonists (cyproterone acetate, hydro- disease is evident from its continued expression in a xyflutamide and bicalutamide). This study provides a large proportion of resistant cases, as well as from the comprehensive analysis of androgen-regulated gene ex- detection of AR gene amplification and activating pression in the LNCaP prostate cancer cell line, and mutations in the AR gene and/or activation of AR identifies a number of androgen-regulated genes, not through crosstalk with other signalling pathways described previously, as candidates for mediating andro- (Feldman and Feldman, 2001; Taplin and Balk, 2004; gen responses in prostate cancer cells. Agoulnik and Weigel, 2006). Oncogene (2009) 28, 2051–2063; doi:10.1038/onc.2009.68; Androgen binding by the AR leads to its recruitment published online 13 April 2009 to specific gene promoters and consequent regulation of gene expression (Shang et al., 2002; Dehm and Tindall, Keywords: prostate cancer; LNCaP cells; androgens; 2006). Gene-expression microarray analysis allows the anti-androgens; real-time RT–PCR; microarrays global interrogation of the complete genome for the determination of changes in gene expression, thereby permitting the identification of gene networks that may be important in mediating AR-regulated prostate-cancer ONCOGENOMICS Introduction cell growth, thus providing a clearer understanding of the AR function in prostate cancer, and identifying new Normal male development and growth requires the prognostic markers and therapeutic targets. In order to action of androgens. These hormones function by identify androgen-responsive genes in prostate cancer activating the androgen receptor (AR), a member of cells, we used the LNCaP cell line as it expresses AR, the ligand-activated nuclear receptor superfamily of shows androgen-regulated expression of androgen- transcription factors (Brinkmann et al., 1999; Lu et al., responsive genes, such as the prostate cancer biomarker PSA, grows in an androgen-regulated manner in cell culture and forms androgen-dependent tumours in Correspondence: Drs S Ali and L Buluwela, Department of Oncology, xenograft models (Sobel and Sadar, 2005). Earlier Imperial College London, Du Cane Road, London W1 0NN, UK. microarray studies for profiling androgen-regulated E-mail: [email protected] or [email protected] Received 4 August 2008; revised 25January 2009; accepted 4 March genes in prostate cancer cell lines have been carried 2009; published online 13 April 2009 out using the synthetic androgen R1881 or dihydro- Androgen-regulated gene expression in LNCaP cells S Ngan et al 2052 testosterone (DHT), but few studies have carried out and 300 annotated genes whose expression is up- and a detailed investigation of AR-regulated gene downregulated by R1881, respectively (Supplementary expression, in response to anti-androgens (for a review Table 1). see Dehm and Tindall, 2006). In addition, AR activity can be stimulated by oestrogen (E2) and progesterone, Functional categories and pathways for genes regulated whereas the anti-androgen cyproterone acetate (CPA) by R1881 is a partial agonist for AR (Doesburg et al., 1997). As described above, 70% of the upregulated genes and Finally, some AR mutations, such as the AR-T877A 78% of the downregulated genes encode proteins with a mutation in LNCaP cells, increase the agonist activity of known or an inferred function. These gene lists were some of these weak AR agonists, as well as the anti- analysed for gene ontology (GO) within the ‘molecular androgens CPA and hydroxyflutamide (OHF) (Steketee function’ principal group (http://www.geneontology. et al., 2002). However, detailed analysis of the expres- org/). In order to maximize information from this sion of androgen-regulated genes in response to the analysis, gene ontology classifications for subcategories weak agonists and AR antagonists !been confined, by within the two largest categories; namely ‘binding’ and and large, to reporter gene studies (Brooke et al., 2008). ‘catalytic activity’, were also determined. The collective To gain new insight into the regulation of gene results from this ontology analysis show that 38 gene expression by AR, we carried out microarray profiling in ontology classifications are represented, which, by LNCaP cells treated with R1881 and Q-RT–PCR proportion, show a similar distribution in the R1881 analysis for the genes whose expression is stimulated upregulated and downregulated gene sets (Figure 1a). and for a proportion of the genes whose expression is The exception to this is the signal transducer activity inhibited by R1881, over a time course of R1881 grouping (GO: 4871), which functionally represents a treatment, and after the treatment of LNCaP cells with higher proportion of R1881 downregulated genes (4.6% other agonists and anti-androgens. representation in the upregulated gene set, compared with 9.3% in the downregulated set). The R1881 upregulated and downregulated gene lists were further combined to generate an R1881 regulated Results and discussion gene set and were analysed by functional annotation, using web-based tools provided by the Database for Identification of genes whose expression is regulated Annotation, Visualization, and Integrated Discovery by R1881 (DAVID) resource (http://david.abcc.ncifcrf.gov) (Dennis To perform gene-expression microarray analysis of et al., 2003; Huang da et al., 2007). This resulted in the prostate-cancer cells treated with the synthetic androgen identification of 64 functional annotation clusters with R1881, RNA prepared from three bio-replicate cultures enrichment scores in the range 0.01–2.43, with three of LNCaP cells treated with R1881 for periods of time functional pathway clusters having enrichment scores ranging from 4 to 72 h was evaluated for the R1881 >1 (Figure 1b). stimulation of expression of four well-characterized The most significant functional-pathway cluster iden- androgen-regulated genes (PSA, TMPRSS2, NDRG1 tified within this gene list was found to be one in which and GREB1). Expression of these genes was stimulated major determinants of the transforming growth factor within 4 h after R1881 addition and levels continued to (TGF)-b signalling pathway, including SMAD1, increase up to 24 h, after which time expression was SMAD3, SMAD6 and SMAD7, were downregulated, reduced, but remained high up to 72 h (Supplementary whereas ID3, a candidate gene for metastatic prostate Figure 1). On the basis of these results, RNA from each cancer (Burmester et al., 2004; Yuen et al., 2006), was of the three replicates, for 24-h time points, was chosen upregulated. Although it has been reported that TGF-b for hybridization to the Applied Biosystems (ABI, signalling is downregulated in prostate cancer, this has Foster City, CA, USA) human genome survey micro- largely been attributed to transcriptional regulation of array V2.0, which has probe sets for 29 098 genes. Raw TGF-b expression by AR (Qi et al., 2008), or through data were quality-assessed and filtered according to
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