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From the Departments of Urology,* Pathology, Epidemiology and Biostatistics, and the Department of Medicine, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York; and the Department of Medicine,¶ Joan and Sanford I. Weill College of Medicine of Cornell University, New York, New York
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Abstract |
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220,900 individuals in 2003.1
More than 1 million men older than the age of 50 alive today are expected to die of this disease. The incidence of prostate cancer has increased sharply in the last decade as serum prostate-specific antigen testing has become widely available.2
This is primarily because of detection of asymptomatic and early-stage disease. These organ-confined prostate cancers are potentially curable with surgery or radiation. On the other hand, locally advanced tumors and metastatic prostate cancers are much more difficult to treat and in many cases lethal. Androgens play a critical role in normal prostate function and in the development and progression of prostate cancer.3-6 Androgenic hormones act as ligands and are able to bind to and activate the intracellular androgen receptor (AR). Ligand binding to the AR results in conformational changes, dissociation from chaperones, phosphorylation, homodimerization, and subsequent interactions with specific androgen response elements (ARE) in the promoter regions of androgen-targeted genes. Transcriptional activity is dependent on the release of repressors and the recruitment of co-activators. Other growth factor mediated signal transduction pathways may also influence androgen signaling.7 These critical interactions and multisubunit complexes are likely to be responsible for the diversity of androgen-regulated functions and cell context specificity. The expression of androgen-responsive genes determines the balance between cell proliferation, cell death, and differentiation of normal prostatic epithelia and is believed to similarly affect neoplastic prostate cells.8 Despite the importance of the androgen response pathway in prostate cellular function, relatively few downstream targets and pathways have been identified and characterized.
Prostate cancer cells are typically androgen-dependent and androgen ablation is the standard systemic therapy for this disease. Androgen deprivation induces programmed cell death in normal, hyperplastic, preneoplastic, and malignant prostatic epithelial cells.6 Ablation can be achieved surgically by orchiectomy or chemically with gonadotropin-releasing hormone analogues, exogenous estrogens, progestational agents, anti-androgens, or adrenal steroid synthesis enzyme inhibitors. Virtually all prostate cancer patients treated with androgen ablation respond but eventually develop resistance, an ominous clinical state for which no consistently effective therapy exists.8
The critical molecular mechanisms by which prostate cancer cells become resistant to hormone therapy are primarily unknown, but several hypotheses exist. Amplification or mutation of the AR occurs in 20 to 30% of androgen ablation-resistant prostate cancers (AARPCs) suggesting that tumor cells become hypersensitive and respond to low levels of androgens or become promiscuous and can be stimulated by alternative ligands with structural homology to androgen.6,9 An alternative model for therapy resistance suggests that recruitment of nonsteroid receptor signal transduction pathways can activate the androgen response in the setting of clinical androgen deprivation.7 A more complete basic understanding of AARPC and new effective therapies are needed.
Study of the complex processes associated with androgen signaling and hormone-resistant progression in prostate cancer has proved difficult because few models exist that reproducibly mimic the clinical course of the disease in men. Many studies are based on a small repertoire of cell lines of uncertain relevance to primary disease. To characterize the androgen response program in human prostate cancer we performed a genome-wide analysis and identified gene expression changes that occur during androgen ablation therapy and in resistant disease. These expression profiles provide new insight into the biology of the androgen response program and the mechanisms of therapy resistance.
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Materials and Methods |
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Prostatic tissues were obtained from therapeutic or diagnostic procedures performed as part of routine clinical management at the Memorial Sloan-Kettering Cancer Center, New York, NY. Samples included 5 benign prostate tissues from the peripheral zone of prostatectomies of cancer patients, 23 primary prostate cancers from patients undergoing radical prostatectomy with no therapy before surgery, 17 primary prostate cancers after 3 months of androgen ablation therapy (a monthly injection of 3.6 mg of goserelin and 250 mg of flutamide three times daily for 3 months before radical prostatectomy), and 9 metastatic prostate cancers, including 3 that were progressing after 5 to 10 years of androgen ablation (see Supplemental Table 1
at www.amjpathol.org for clinical details). Tissues were snap-frozen in liquid nitrogen and stored at -80°C. Each sample was examined histologically using hematoxylin and eosin-stained cryostat sections. Tissues of interest were manually dissected from the frozen block. Care was taken to remove nonneoplastic tissues from tumor samples. Tumor samples contained 60 to 80% prostate cancer cell nuclei based on histological assessment. All studies were conducted under Memorial Sloan-Kettering Cancer Center Institutional Review Board-approved protocols.
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Gene Expression Analysis
Total RNA was extracted from frozen tissues by homogenization in guanidinium isothiocyanate-based buffer (Trizol; Invitrogen, Carlsbad, CA), purified using RNA easy (Qiagen, Valencia, CA) and evaluated for integrity by denaturing agarose gel. Complementary DNA was synthesized from total RNA using a T7-promoter-tagged oligo-dT primer. RNA target was synthesized by in vitro transcription and labeled with biotinylated nucleotides (Enzo Biochem, Farmingdale, NY). Labeled target was assessed by hybridization to Test2 arrays (Affymetrix, Santa Clara, CA) and detected with phycoerythrin-streptavidin (Molecular Probes, Eugene, OR) amplified with anti-streptavidin antibody (Vector, Burlingame, CA). Gene expression analysis was performed using Affymetrix U95 human gene arrays with 63,175 features for individual gene/expressed sequence tag clusters using instruments and protocols recommended by the manufacturer. The U95 set consists of five distinct microarrays (A through E), each containing probes for 12,000 gene/expressed sequence tag transcripts. Two response measures, the average difference and absolute call, were extracted for each gene on every sample, as determined by default settings of Affymetrix Microarray Suite 4.0. Average difference was used as the primary measure of expression level, and absolute call was retained as a secondary measure. Expression values on each array were multiplicatively scaled to have an average expression of 2500 across the central 96% percent of all genes on the array.
Data Analysis
For oligonucleotide arrays, scanned image files were visually inspected for artifacts and analyzed using Microarray Suite v4.0. Uniformly and strongly differentially expressed genes were determined by the following approach (fully described in supplementary information). The expression data set was first filtered to include only those probe sets detecting genes with mean expression values that differed by at least threefold between groups. Probes were then ranked based on the relative magnitude of the difference (t-test) between the means of any two sample sets. A Mann-Whitney test was used in place of the t-test when comparing small numbers of samples. Data sets used for hierarchical clustering were normalized by standardizing each gene and sample (array) to mean = 0 and variance = 1. Average linkage hierarchical clustering and result display were performed using Cluster and TreeView software.10 Specific genes corresponding to individual probe sets were identified using the Affymetrix database (https://www.affymetrix.com/index.affx) to identify the GenBank accession number of the clone used to produce the oligonucleotide probe set and annotated through review of internet resources (Genecards, http://nciarray.nci.nih.gov/cards/; Locus Link, http://www.ncbi.nlm.nih.gov/LocusLink//index.html; Online Mendelian Inheritance in Man, http://neptune.nlm.nih.gov/entrez/query.fcgi?db = OMIM; Gene Ontology Browser, http://cgap.nci.nih.gov/Genes) and publications identified in Pubmed (http://www.ncbi.nlm.nih.gov/PubMed/).
Identification of ARE Motifs
Reference sequence accession numbers were identified for 80 genes with differential expression in both human tumors and LNCaP cells after androgen withdrawal by search of the Affymetrix database and the Ref_Seq database at the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/LocusLink/refseq.html/). The reference sequences were used to query the assembled human genome sequence (http://genome.ucsc.edu/) and 5 kb of sequence 5' to the transcription start site of each gene was retrieved. Each sequence was analyzed for homology to the consensus ARE motif 5'-AGAACAnnnTGTTCT-3' using the Filtered String-based Search Query of TESS (http://www.cbil.upenn.edu/tess). In the "Factor Filter" section, we choose class 2.1.1.3 for AR according to transcription factor classification (http://www.gene-regulation.com/pub/databases/transfac/cl.html). In the "Score Filters" section, the "Maximum Allowable String Mismatch %" was set to 20%, all of the other parameters were set the same as default. Motifs with at least 10 identities of the 12 consensus ARE nucleotides were reported.
Immunohistochemistry
Multitissue blocks of formalin-fixed, paraffin-embedded tissue corresponding to the samples used in this analysis were prepared using a tissue arrayer (Beecher Instruments, Silver Spring, MD). The blocks contained three representative 0.6-mm cores from diagnostic areas of each case. Immunohistochemical detection of prostate-specific antigen (1:2000; Biogenex, San Ramon, CA), AR (1;50; DAKO, Carpinteria, CA), squalene monooxygenase (1/4000; gift of Dr. Todd D. Porter, University of Kentucky, Lexington, KY) was performed with standard streptavidin-biotin-peroxidase methodology using formalin-fixed, paraffin-embedded tissue and microwave antigen retrieval as described.11
Fluorescent in Situ Hybridization
Bicolor fluorescent in situ hybridization studies were performed on paraffin sections using commercially available probes for AR (Vysis, Downer’s Grove, IL) and chromosome X centromere-specific alphoid region (Vysis). Fluorescent in situ hybridization was performed as described.12 The number of hybridization signals for each probe was assessed in an average of 36 nuclei with strong and well-delineated signals. As controls, normal peripheral blood lymphocytes were simultaneously hybridized.
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Results and Discussion |
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TopAbstractMaterials and MethodsResults and DiscussionConclusion and Clinical...References |
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The development and progression of prostate cancer is dependent on androgenic hormones. Androgens normally regulate transcription of genes involved in critical cellular pathways controlling cell proliferation, differentiation, and programmed death. The specific transcriptional targets of the AR that mediate these biological programs for prostate cancer are unknown. To identify genes that are responsive to androgens, we performed comprehensive expression analysis of resected prostate carcinomas and nonneoplastic prostate tissues from patients that had been treated with a standardized regimen of androgen ablation therapy and compared those to expression profiles of similar tissues from patients that had not been treated. All tumor samples were evaluated histologically and tissue blocks trimmed to provide a consistent prostate cancer cell content of between 60% and 80%. The morphological features typical of androgen ablation therapy were evident in neoadjuvant-treated cases (Figure 1
and Supplemental Table 1 at www.amjpathol.org) and resulted in slightly different nonneoplastic cell content between the sample groups.13
The trimming of frozen tissue blocks and stringent criteria for differential expression (described below) were designed to take this into account.
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54,000 genes and expressed sequence tags. Seventeen patients received neoadjuvant hormonal ablation therapy with goserelin and flutamide for 3 months (hereafter referred to as "treated" cases), and 23 patients received no neoadjuvant therapy (untreated). General levels of gene expression for the two groups were similar. Sixty-four percent of the 63,175 probe sets detected expression in at least 1 of the 23 untreated prostate cancer samples based on the Microarray Suite 4.0 present/absent algorithm. Of the 17 treated cases, 61.9% of the probe sets had a present call in at least one of the samples. In contrast, analysis of gene expression in the LNCaP prostate carcinoma cell line cultured in androgen-supplemented media demonstrated a present call for 50.2% of the probe sets, and with androgen withdrawal a present call was made 50% of the time. The greater diversity of transcripts in native prostate cancer likely reflects cell type heterogeneity in human tissues.
Comparison of expression profiles using a hierarchical clustering algorithm demonstrated a strong tendency to subgroup the samples with respect to treatment status (Figure 2A)
. This suggests that distinct, consistent differences in transcript levels occur in prostate cancers as a result of androgen deprivation. We used a stringent filter to identify genes that were strongly differentially expressed with androgen ablation therapy. A total of 654 of the 63,175 probe sets detected a difference of at least threefold between the mean expression values for treated and untreated tumors with a t-test P value of less than 0.001 (see Supplemental Table 2 at www.amjpathol.org for entire gene list). Two hundred ninety genes were up-regulated with androgen ablation therapy and 364 genes were down-regulated. Of these 654 probe sets, 512 (78.3%) detected similar directional alteration in gene expression after therapy in samples of adjacent nonneoplastic prostate enriched for epithelium and 336 of these further showed a threefold change. This suggests that many of the gene expression changes after therapy in prostate cancer represent a physiological response to androgen withdrawal that also occurred in nonneoplastic prostate. Others may be part of a tumor-specific androgen response program.
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Identification of Genes Likely to Be Directly Regulated by Androgen
The data described above reflect gene expression in human prostate cancer after 3 months of androgen ablation and it is not possible to distinguish those changes that occur early and may correspond to direct targets of the AR, from those that occur at a later time and most likely represent subsequent events. To identify differentially expressed genes that were likely to be directly regulated by the activated AR we used the androgen-responsive LNCaP cell line to characterize changes in transcript levels that occur rapidly after androgen withdrawal and compared that to the data from human tumors. Expression profiles of LNCaP cells growing in R1881 (a synthetic androgen analog)-supplemented media were compared to profiles of cells 36 hours after transfer to androgen-depleted media. One hundred forty-nine of the 654 genes (22.8%) that were strongly differentially expressed in prostate cancer with androgen-ablation therapy also showed at least a twofold change in transcript level in LNCaP cells after androgen withdrawal (Supplemental Table 2 at www.amjpathol.org). In contrast, less than 1% of probe sets demonstrated a twofold change in a replicative hybridization of RNA from androgen-supplemented LNCaP. Genes with quantitative mRNA changes occurring within hours of androgen withdrawal are more likely to be direct targets of the activated AR and include the prototypical androgen response gene KLK3. However some of the expression changes could be because of secondary events after androgen withdrawal.
To further explore the potential as a direct target gene of the AR, we analyzed the 5' regulatory region of 80 of the 149 genes that were strongly differentially expressed in both human tumors and LNCaP for which reference sequence information was available. Motifs with a high degree of homology to the consensus ARE were identified in 20 genes (Table 1)
suggesting the potential for AR binding. This subset of differentially expressed genes is likely to represent direct and very early downstream targets of the androgen response program in human prostate cancer.
Several high-throughput methods have been previously used to address the androgen response program in LNCaP cells.14-18
This cell line expresses a functional although mutated AR, proliferates in response to androgens, and produces prostate-specific antigen in an androgen-dependent manner. Most studies have analyzed cells within hours of androgen manipulation and many differentially expressed genes have been identified in common. It is interesting to note that 25% of the differentially expressed, named genes in our study of human prostate cancers have also been shown to have significant changes in expression after short-term androgen manipulation of LNCaP cells.17,18
This degree of concordance using diverse experimental systems and technical platforms serves to validate that many of the genes identified in this analysis are truly androgen regulated.
Changes in Gene Expression Related to Androgen Ablation-Resistant Progression of Prostate Cancer
After an initial response to therapy most patients develop progressive disease resistant to androgen ablation. The molecular mechanisms underlying this clinically important transition to androgen ablation resistance are poorly understood. To characterize gene expression changes that occur as part of the resistance mechanism we compared gene expression in resistant tumors to samples from patients that had not developed resistance. These are rare clinical samples, however the three AARPC samples represent tumors that were progressing in the setting of undetectable serum testosterone and long-term androgen ablation. Of particular interest, hierarchical cluster analysis revealed that the overall expression patterns for these androgen-independent tumors were more similar to that of the untreated, androgen-dependent primary cancers than to tumors under conditions of androgen deprivation such as the neoadjuvant androgen ablation-treated cases described above (Figure 2B)
. This suggested a reversal of many of the expression changes because of androgen ablation possibly through reactivation of the androgen response pathway as suggested by others.20-23
In fact the vast majority of genes that were identified as differentially expressed with short-term androgen ablation did not demonstrate changes to the same extent in AARPC even though these tumors were also in an androgen-poor environment. However, a unique set of genes was differentially expressed in resistant tumors. A total of 304 of the 63,175 U95 probe sets detected tumor-related differential gene expression between primary androgen-dependent and metastatic hormone-resistant tumors of at least threefold with a Mann-Whitney test P value <0.001 (see Supplemental Table 3 at www.amjpathol.org for entire gene list). Because there are marked differences in gene expression between primary and metastatic prostate cancer regardless of treatment status,11
we further identified the subset of these genes that were also differentially expressed between metastatic AARPC and other metastatic prostate cancers. One hundred of the 304 genes were also differentially expressed threefold in hormone-resistant metastatic tumors (n = 3) compared to androgen-dependent metastatic tumors (n = 6) (Table 2)
. Thirty-three were up-regulated and 67 were down-regulated in the resistant tumors.
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. Analysis of a larger set of AARPCs by immunohistochemistry demonstrated a high level of nuclear-localized AR protein in 26 of 28 additional cases of AARPC (Figure 3, B and C)
. The level of expression was increased relative to that seen in the majority of primary untreated prostate cancers. Because gene amplification is a known mechanism by which AR could be overexpressed, we performed fluorescent in situ hybridization for the AR gene and found that none of the AARPC analyzed by microarray and only 8 of 29 additional AARPC cases with high levels of AR expression had increased gene copy number (Figure 3, D and E)
. This data and other published series24-26
suggest that strong expression of the AR is present in most cases of AARPC and for many tumors the increase in AR transcript levels occurs by mechanisms other than gene amplification. Overexpression of the AR could contribute to reactivation of the androgen response pathway in resistant tumors through increased sensitivity to low levels of ligand or as a cooperative effect with ligand independent pathways of AR activation.27
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. This included one of the rate-limiting enzymes in sterol synthesis, squalene monooxygenase.28
By semi-quantitative immunohistochemistry we were able to demonstrate that immunoreactive squalene monooxygenase was produced by prostate cancer tumor cells (Figure 5)
and the level of immunoreactivity generally correlated with RNA levels in a small number of cases available for study (data not shown). In addition strong immunoreactivity for squalene monooxygenase was detected in a separate subset of AARPC in contrast to nonresistant tumors that in general had lower levels. This result implies that essential enzymes have been up-regulated in a manner that would facilitate endogenous production of steroids in some cases of AARPC. Increased availability of androgenic ligands would provide a compensatory mechanism for overcoming androgen deprivation that complements increased sensitivity as a result of AR overexpression. If in fact this pathway is proven to contribute to resistance, it is encouraging that drugs to inhibit squalene monooxygenase have been developed.28
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Conclusion and Clinical Implications |
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Acknowledgements |
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Footnotes |
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Supported by the National Institutes of Health (grant U01 CA84999 to W. G.).
Present address of J. H.: Department of Surgery, University of Kansas Medical Center, Kansas City, KS.
Present address of E. L.: Department de Pathologie, Hotel Dieu de Quebec, Quebec, P. Quebec, Canada, G1R 2J6.
Accepted for publication September 25, 2003.
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