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-Methylacyl-CoA Racemase
Brady Urological Institute [J. L., S. Z., T. A. D., C. M. E., W. B. I., A. M. D.] and Department of Pathology [W. R. G., J. L. H., C. J. B., A. M. D.], Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287; Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland 21205 [E. A. P.]; National Human Genome Research Institute, NIH, Bethesda Maryland 20892 [J. M. T.]; and Departments of Pediatrics, Emma Children’s Hospital, Clinical Chemistry, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands [S. F., R. J. W.]
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-methylacyl-CoA racemase (AMACR), whose expression is consistently up-regulated in prostate cancer. Analysis of mRNA levels of AMACR revealed an average up-regulation of 
9 fold in clinical prostate cancer specimens compared with normal. Western blot and immunohistochemical analysis confirms the up-regulation at the protein level and localizes the enzyme predominantly to the peroxisomal compartment of prostate cancer cells. A detailed immunohistochemical analysis of samples from 168 primary prostate cancer cases using both standard slides and tissue microarrays demonstrates that both prostate carcinomas and the presumed precursor lesion (high-grade prostatic intraepithelial neoplasia) consistently scored significantly higher than matched normal prostate epithelium; 88% of the carcinomas had a staining score higher than the highest score observed for any sample of normal prostate epithelium. Both untreated metastases (n = 32 patients) and hormone refractory prostate cancers (n = 14 patients) were generally strongly positive for AMACR. To extend the utility of this marker for prostate cancer diagnosis, we combined staining for cytoplasmic AMACR with staining for the nuclear protein, p63, a basal cell marker in the prostate that is absent in prostate cancer. In a simple assay that can be useful for the diagnosis of prostate cancer on both biopsy and surgical specimens, combined staining for p63 and AMACR resulted in a staining pattern that greatly facilitated the identification of malignant prostate cells. The enzyme encoded by the AMACR gene plays a critical role in peroxisomal ß oxidation of branched chain fatty acid molecules. These observations could have important epidemiological and preventive implications for prostate cancer, as the main sources of branched chain fatty acids are dairy products and beef, the consumption of which has been associated with an increased risk for prostate cancer in multiple studies. On the basis of its consistency and magnitude of cancer cell-specific expression, we propose AMACR as an important new marker of prostate cancer and that its use in combination with p63 staining will form the basis for an improved staining method for the identification of prostate carcinomas. Furthermore, the absence of AMACR staining in the vast majority of normal tissues coupled with its enzymatic activity makes AMACR the ideal candidate for development of molecular probes for the noninvasive identification of prostate cancer by imaging modalities. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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High-throughput gene expression profiling using cDNA microarray allows for systematic interrogation of transcriptionally altered genes. By comparing the mRNA expression profile of cancerous lesions with noncancerous lesions, multiple candidates of molecular markers for prostate cancer have emerged (2, 3, 4, 5, 6)
. One such candidate, the gene for AMACR,3
was identified as being overexpressed in prostate carcinoma cells when compared with benign or normal prostate epithelial cells (2
, 3)
. AMACR is a well-characterized enzyme (7)
that plays a key role in peroxisomal ß-oxidation of dietary branched-chain fatty acids and C27-bile acid intermediates. It catalyzes the conversion of (R)--methyl-branched-chain fatty acyl-CoA esters to their (S)-stereoisomers. Only the (S)-stereoisomers can serve as substrates for branched-chain acyl-CoA oxidase during their subsequent peroxisomal ß-oxidation. Two aspects of this pathway may have particular relevance for prostate carcinogenesis: (a) the main sources of branched chain fatty acids in humans (milk, beef, and dairy products; Ref. 8
) have been implicated as dietary risk factors for prostate cancer (9)
; and (b) peroxisomal ß-oxidation generates hydrogen peroxide (10)
, a potential source of procarcinogenic oxidative damage (11
, 12)
.
An initial report by Xu et al. (2)
, using a limited number of samples, indicated that AMACR was overexpressed potentially in a subset of prostate cancers at both the mRNA and protein level. Our previous study compared gene expression profiles of 16 prostate cancer and 9 samples of BPH using cDNA microarrays containing 6500 human genes (3)
. AMACR was expressed highly in the majority of prostate cancer samples, averaging 6-fold higher levels than the BPH samples. In this study, we expanded these previous studies by including cDNA microarray data from an additional 35 prostate tissue samples, comprising matched normal tumor pairs, and by performing an extensive IHC analysis of both primary and metastatic prostate cancer specimens, including normal and cancerous prostate tissue from 159 patients analyzed on prostate TMAs. Furthermore, we examined the diagnostic utility of combining staining for AMACR with staining for p63, a prostate basal cell marker that is absent in the vast majority of prostate cancers (13
, 14)
. The consistent and extensive up-regulation of AMACR that we observe at both the mRNA and protein level strongly suggests that AMACR will be an important new marker for prostate cancer.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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60% (range from 60 to 90%) adenocarcinoma cells in cellular composition, and the normal samples were estimated to contain 50% (range from 50 to 75%) epithelial cells. Institutional Review Board-approved informed consent was obtained from all patients in this study.
cDNA Microarray Analysis.
RNA extraction, labeling, and hybridization were carried out as described previously (3)
. A single reference sample composed of a pool of RNA from two BPH specimens was used throughout all hybridizations. Measurement values were extracted for normalized ratios of signal intensities of sample versus reference, which represent the relative mRNA abundance for each gene in each sample when compared with the common reference (3)
.
Real-time Reverse Transcription-PCR.
Quantitative PCR was performed on iCycler (Bio-Rad, Richmond, CA) with gene-specific primers (AMACR: 5'-GAATCCGTATGCCCCGCTGAATCT-3' and 5'-ACCCTTGCCAGTGCGTGTGC-3'; TBP: 5'-CACGAACCACGGCACTGATT-3' and 5'-TTTTCTTGCTGCCAGTCTGGAC-3'), as described previously (16)
. A standard curve was generated by serial dilution of plasmids containing the specific amplicons assayed. AMACR mRNA copy number was normalized to TBP.
Western Blot Analysis.
Protein (25 µg) was subjected to SDS–polyacrylamide (10%) gel electrophoresis, transferred to nitrocellulose (Amersham Pharmacia Biotech, Piscataway, NJ), probed with AMACR antiserum (7)
at a 1:2000 dilution, and detected by enhanced chemiluminescence (Amersham Pharmacia Biotech) as described previously (16)
.
TMAs: Construction and Analysis.
A total of 159 radical prostatectomy specimens were selected randomly out of a total of >400 cases performed between 1/1/2000 and 8/1/2001 at Johns Hopkins Hospital and used to construct TMAs as described previously (16)
. Areas representing the largest carcinoma present, as well as areas of normal appearing prostate epithelium, were circled on the glass slides. For each sample of tumor and normal, four tissue cores were taken for TMA construction. Although there is no universal method of sampling prostate cancer tissue for IHC studies, using either standard slides or TMAs, the histological features of these areas that we sampled generally reflect the final Gleason score for the case. Stained TMA slides were scanned using the BLISS imaging system as described by Manley et al. (17)
. Each array spot was then formed into a composite image and viewed and scored on a personal computer monitor as described (16)
. Data were then further summarized, and statistical analysis was performed using Stata 6.0 and SAS for Microsoft Windows.
Prostate Adenocarcinoma Tissue from Standard Slides.
For a number of the cases, standard slides were used to assess overall percentage of positive cells in the tumors and normal tissues and also to further evaluate expression in HGPIN and BPH.
Metastatic Prostate Cancers.
For metastatic carcinoma, standard slides from specimens (pelvic lymph node, soft tissue, and bone metastases) from patients with nonhormone refractory tumors were obtained from the archives of the Department of Pathology at The Johns Hopkins University. For hormone refractory cancer specimens, tissues were obtained as a single TMA from the University of Michigan, Specialized Programs of Research Excellence core tissue facility.
IHC Staining.
Staining for AMACR was carried out using the Envision+ kit (DAKO Corp., Carpinteria, CA). Briefly deparaffinized slides were hydrated and then placed in citrate buffer (pH 6.0) and steamed for 14 min. Endogenous peroxidase activity was quenched by incubation with DAKO peroxidase block for 5 min at room temperature. Slides were then washed and incubated with primary antibody (1:16,000 dilution of antiserum) overnight at 4°C. Secondary antirabbit antibody-coated polymer peroxidase complex was applied for 30 min at room temperature. Substrate/chromogen was applied and incubated for 5–10 min at room temperature. Slides were counterstained with hematoxylin. For double labeling of AMACR and p63, the anti-p63 mouse monoclonal antibody cocktail (1:100 dilution; Lab Vision Corp., Fremont, CA) was added after the anti-racemese antibody incubation and incubated for 45 min at room temperature. The secondary antirabbit and antimouse HRP conjugates were sequentially added, and the reaction was developed as above.
Scoring of IHC Staining.
A scoring method was based on the fact that the specimens clearly showed a varying degree of staining intensity and percentage of cells staining. Therefore, a combined intensity and percentage positive scoring method was used (18)
. Strong intensity staining was scored as 3, moderate as 2, weak as 1, and negative as 0. For each intensity score, the percentage of cells with that score was estimated visually. A combined weighted score consisting of the sum of the percentage of cells staining at each intensity level was calculated for each sample, e.g., a case with 70% strong staining, 10% moderate staining, and 20% weak staining would receive a score as follows: (70 x 3 + 10 x 2 + 20 x 1) = 250. The maximum score is 300.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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, the majority (20 of 23) of the cancer samples demonstrated overexpression of AMACR mRNA compared with the BPH reference. When the cancer samples were compared with their matching normal samples, AMACR was overexpressed in the cancer samples in 9 of 12 pairs. Moderate overexpression compared with the reference (an average of 3-fold) was also observed in 3 of the 12 normal samples. Consistent with previous reports, GSTP1 expression was down-regulated in the majority of cancer samples compared with BPH reference or their matching normal samples. Expression of KRT8, an epithelial marker, showed little variation among all of the samples, indicating that the sample preparation was effective to enrich and balance the epithelial content in the samples analyzed.
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Western Blot Analysis of AMACR Protein.
Expression of AMACR protein was examined using an antiserum demonstrated previously to be specific for this antigen (7)
. Western blot detection of AMACR in liver, as a positive control (7)
, and a series of prostate tissue samples is shown in Fig. 2
. Although a Mr 47,000 band corresponding to AMACR protein was readily detected in liver and each of the prostate cancer specimens, little or no reactivity was observed in the corresponding normal specimens or any of the BPH samples assayed.
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). Prostate stroma, inflammatory cells, endothelial cells, and nerves were uniformly negative (Fig. 3)
. Strikingly, adenocarcinomas showed highly intense staining in the majority of tumor cells in most cases (n = 19 carcinoma lesions from 14 patients, median = 290, mean = 277, SD = 30; Fig. 3
). The staining was uniformly cytoplasmic and was typically found in small punctate, microbody structures, consistent with the previously reported localization of AMACR predominantly to peroxisomes and mitochondria (7)
. Staining in HGPIN was also generally positive, although the staining was more variable and often less intense than adjacent carcinoma (Fig. 3, C and D
; n = 10 areas from 6 patients, median 170, mean 179, SD = 63). Staining in atrophic areas was generally negative or positive in a small percentage of cells (n = 5 areas from 3 patients, median = 30, mean = 30, SD = 22). Staining in BPH was generally negative or focally, weakly positive (n = 6 areas from 4 patients, median = 20, mean = 20, SD = 8.9).
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For normal prostate and adenocarcinoma, between 2.5 and 3 TMA spots (duplicate spots) were scored from each patient. For statistical analyses, the mean of the individual spot scores were computed so that for each tissue type from each patient, there was a single IHC score for comparison. Using these mean scores, the AMACR IHC scores for both carcinoma and HGPIN were highly statistically significantly different from normal (Fig. 4
, carcinoma versus normal, P < 0.0001; HGPIN versus normal, P < 0.001, Wilcoxon’s rank-sum test). The score for HGPIN was significantly less than the score for carcinoma (P = 0.0002, Wilcoxon’s rank-sum test). If a cutoff of 100 is used for positive staining, then 95.6% of carcinomas were positive, whereas 3.5% (5 of 144) of normal epithelium was positive. Using a score of 150 for strong positive staining, then 88% of the carcinomas would be considered strong, versus none of the normal epithelium. The carcinomas (52%) had a median score of 300 (the maximum).
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. There was no relation between AMACR IHC score and Gleason grade, pathological stage, patient age, or preoperative serum prostate-specific antigen (Kruskal-Wallis, all Ps > 0.05). As expected, Gleason score at radical prostatectomy was associated strongly with higher stage disease (Spearman’s rank correlation coefficient = 0.42, n = 142, P < 0.0001; Table 1
).
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AMACR Protein Expression in Other Normal Tissues.
To examine the overall tissue distribution of AMACR protein expression, staining was performed using a TMA containing a wide variety of human tissues. Staining was strongly positive in virtually all hepatocytes, proximal kidney tubules, and glomerular epithelial cells of the kidney (data not shown). Moderate staining was found in the acinar cells and some ductal cells of major salivary glands. Weak staining was found in distal tubules and collecting ducts of the kidney. Other tissues showed weak and heterogeneous expression, including the following: (a) neurons in the central nervous system; (b) absorptive and paneth cells of the small bowel; (c) absorptive cells of the large bowel; and (d) Sertoli cells of the testis. Staining was not detectable in the urinary bladder, ovary, endometrium, fallopian tube, uterine cervix, breast, lung, skin, tonsil, lymph nodes, thymus, spleen, laryngeal epithelium, minor salivary glands, pancreas, gall bladder, thyroid, stomach, esophagus, skeletal muscle, or smooth muscle.
Combination of AMACR Staining with p63 Facilitates Detection of Prostate Cancer Cells.
The intense staining in tumors with weak staining in normal suggested that AMACR IHC staining might be useful as an adjunct to the diagnosis of prostate cancer on needle biopsy or other clinical specimens. To be useful as a potential diagnostic marker for prostate cancer, carcinoma lesions need to be separated reliably from lesions of HGPIN and other potential mimicars of prostate cancer, such as adenosis and atrophy, as well as from normal prostate tissue. On small needle biopsy samples, this distinction can sometimes be problematic (21)
. One very useful tool has been IHC staining for basal cell-specific cytokeratins, typically using the 34BE12 monoclonal antibody (22)
. Because basal cells, which are absent in the vast majority of prostatic adenocarcinomas, are present in normal glands, benign mimicars, such as atrophy and adenosis, and in HGPIN, staining for basal cell cytokeratins is often used in prostate cancer needle biopsies (22)
. More recently, the p63 protein has been found to be localized to the nuclei of basal cells in prostate epithelium with a basal cell-specific staining pattern nearly identical to 34BE12 (13
, 14) . Because the staining for p63 is strictly nuclear and is negative in the vast majority of carcinomas, and the staining for AMCAR is cytoplasmic and only strong in carcinoma or HGPIN, we combined the staining for these two markers as a cocktail. There was strong staining of the nuclei of basal cells in benign glands, whereas carcinoma showed no nuclear staining but strong cytoplasmic staining, with no decrease as compared with AMCAR staining alone (n = 20, Fig. 5, A and B
). HGPIN showed variable punctate, cytoplasmic AMCAR staining, but strong and homogeneous nuclear staining in basal cells, thus allowing one to reliably distinguish HGPIN from carcinoma (Fig. 5, C and D)
. At times, HGPIN appeared to contain buds of epithelium, pinching off into the underlying stroma (23)
. An example of this phenomenon is shown in Fig. 5D
(arrow), where a single acinus is projecting from an acinus containing HGPIN. The projecting acinus shows very sparse p63 basal cell staining, consistent with early invasion. The surrounding carcinoma cells show complete loss of p63 staining, yet they contain AMACR cytoplasmic staining.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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In terms of early diagnosis on prostate needle biopsy, whereas basal cell-specific keratin is a useful aid for diagnosis, this marker is lost in prostate cancer. Because there can be artifactual loss of IHC staining, at times, this staining is uninformative and/or misleading. To date, few, if any, validated markers of prostate cancer have been identified that are overexpressed consistently as detected by IHC staining such that they might be of diagnostic use in a large percentage of cases. We now show that AMACR may provide the first example of such a marker. Because AMACR staining can occur intensely in HGPIN, we combined staining using AMACR with staining for p63. Because these markers, when present, are invariably cytoplasmic and nuclear, respectively, there is no need for the use of two color staining. p63 staining has been shown to be comparable with the basal cell-specific keratin 34ßE12 monoclonal antibody but has the advantage in this case of a more clearly discernible nuclear location (13 , 14) . Thus, AMACR is a new positive stain that complements the traditional negative stain to enhance prostate cancer diagnosis. To determine the usefulness of AMACR in diagnostic pathology practice, we have begun to use clinical needle biopsies in prospective studies comparing AMACR, AMACR/p63, and basal cell-specific cytokeratins. Additionally, this marker combination could be of use for nonpathologist researchers studying prostate cancer specimens to enhance diagnostic certainty.
The enzyme encoded by this gene plays a critical role in the metabolism of fatty acid molecules, specifically by peroxisomal ß oxidation (10) . Branched chain fatty acids, which originate almost entirely from the diet, contain methyl groups in the R position, whereas the enzymes of the ß oxidation pathway can only transform substrates having the S configuration (10) . The enzyme AMACR catalyzes this interconversion. One implication of the up-regulation of AMACR is that prostate cancer cells may have a consistently greater capacity to metabolize dietary branched chain fatty acids than would their normal counterparts. Although the contribution of this up-regulation to prostate carcinogenesis, if any, is unclear at present, two interesting aspects of this pathway may be relevant: (a) the first step of the pathway in ß oxidation of branched chain fatty acids is an oxidation step catalyzed by acyl-CoA oxidases, with the products being oxidized substrate and hydrogen peroxide (10) . Experimental overexpression of acyl-CoA oxidase can transform cells (12) , and the increase in oxidative stress because of the production of hydrogen peroxide by this pathway has been proposed to play a role in the transformation process (11) . Indeed, the potent carcinogenic activity of peroxisome proliferators in animal models is thought to be mediated, at least in part, by up-regulation of the peroxide-producing enzymes of the peroxisome (24) ; and (b) the primary branched chain fatty acid whose metabolism is critically dependent on the action of AMACR is phytanic acid, derived from phytol, a breakdown product of chlorophyll in ruminants. This fatty acid is found primarily in cow’s milk, and diary products derived there from, as well as beef but not meat from chickens or some fish (25) . An interesting question is whether the increased risk for prostate cancer conferred by consumption of dairy products and/or red meat (9) is related to the up-regulation of this enzyme and its associated pathway in the early stages of prostate carcinogenesis, e.g., in PIN.
Molecular imaging promises the ability to identify individual cells or groups of cells expressing specific proteins or enzymatic activity in real time in living patients (see Louie et al.; Ref. 26 ) The ability to image AMACR protein or enzymatic activity would likely provide significant value in localization of primary prostate cancer within the prostate. A first application of this would be to help direct the location of needle biopsy sites in the prostate and possibly to assess the extent of cancer within the prostate. In addition, the ability to image AMACR systemically would provide value for detection of metastatic prostate cancer in organs other than the liver and kidney.
The prostate glands of U.S. men are biopsied >1 million times a year, leading to a positive diagnoses of 180,000 new prostate cancer cases annually. Estimates of equivocal or ambiguous biopsy evaluations that are suspicious for cancer range from 0.3 to 24% (21)
, resulting in tens of thousands of repeat biopsies. Clearly, markers, which can assist in the accurate evaluation of prostate needle biopsies, are needed urgently. Because of its consistency and robustness, AMACR appears to fit the criteria for such a marker and as such may become routinely used in the pathological diagnosis of prostate cancer. In addition, the biological function of this marker provides exciting new information regarding the etiology of prostate cancer and provides a novel target for prevention and therapeutics. Whether this marker is pathogenic, a potential drug, or in vivo imaging target is subject to ongoing studies.
While our manuscript was in preparation, Jiang et al. (27) reported overexpression of AMACR by IHC, using a different antibody, in the majority of primary prostate cancers. Although this report did not examine AMACR expression in other tissues, or combine AMACR staining with p63 or evaluate metastatic prostate cancers, the fact that two separate groups simultaneously observe marked overexpression of this protein in primary prostate cancer is a remarkable finding that bolsters the overall importance of AMACR as a new prostate cancer marker.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the Peter Jay Sharp Foundation and PHS Grants CA58236 and CA78588 and a grant from the Charlotte Geyer Foundation. 
2 To whom requests for reprints should be addressed, at Marburg 115, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287.
3 The abbreviations used are: AMACR, -methylacyl-CoA racemase; IHC, immunohistochemical; KRT8, keratin 8; PIN, prostatic intraepithelial neoplasia; TMA, tissue microarray; BPH, benign prostatic hyperplasia; TBP, TATA-binding protein; GSTP1, glutathione S-transferase 
; HGPIN, high-grade prostatic intraepithelial neoplasia.
Received 11/19/01. Accepted 3/ 4/02.
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REFERENCES |
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A. Sreekumar, B. Laxman, D. R. Rhodes, S. Bhagavathula, J. Harwood, D. Giacherio, D. Ghosh, M. G. Sanda, M. A. Rubin, and A. M. Chinnaiyan Humoral Immune Response to {alpha}-Methylacyl-CoA Racemase and Prostate Cancer J Natl Cancer Inst, June 2, 2004; 96(11): 834 - 843. [Abstract] [Full Text] [PDF]
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 K. Savolainen, T. J. Kotti, W. Schmitz, T. I. Savolainen, R. T. Sormunen, M. Ilves, S. J. Vainio, E. Conzelmann, and J. K. Hiltunen A mouse model for {alpha}-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids Hum. Mol. Genet., May 1, 2004; 13(9): 955 - 965. [Abstract] [Full Text] [PDF]
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C. Kumar-Sinha, R. B. Shah, B. Laxman, S. A. Tomlins, J. Harwood, W. Schmitz, E. Conzelmann, M. G. Sanda, J. T. Wei, M. A. Rubin, et al. Elevated {alpha}-Methylacyl-CoA Racemase Enzymatic Activity in Prostate Cancer Am. J. Pathol., March 1, 2004; 164(3): 787 - 793. [Abstract] [Full Text] [PDF]
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M. A. Rubin, M. P. Zerkowski, R. L. Camp, R. Kuefer, M. D. Hofer, A. M. Chinnaiyan, and D. L. Rimm Quantitative Determination of Expression of the Prostate Cancer Protein {alpha}-Methylacyl-CoA Racemase Using Automated Quantitative Analysis (AQUA): A Novel Paradigm for Automated and Continuous Biomarker Measurements Am. J. Pathol., March 1, 2004; 164(3): 831 - 840. [Abstract] [Full Text] [PDF]
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 J. Lapointe, C. Li, J. P. Higgins, M. van de Rijn, E. Bair, K. Montgomery, M. Ferrari, L. Egevad, W. Rayford, U. Bergerheim, et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer PNAS, January 20, 2004; 101(3): 811 - 816. [Abstract] [Full Text] [PDF]
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A. J. Zurita, P. Troncoso, M. Cardo-Vila, C. J. Logothetis, R. Pasqualini, and W. Arap Combinatorial Screenings in Patients: The Interleukin-11 Receptor {alpha} as a Candidate Target in the Progression of Human Prostate Cancer Cancer Res., January 15, 2004; 64(2): 435 - 439. [Abstract] [Full Text] [PDF]
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A J Evans {alpha}-Methylacyl CoA racemase (P504S): overview and potential uses in diagnostic pathology as applied to prostate needle biopsies J. Clin. Pathol., December 1, 2003; 56(12): 892 - 897. [Abstract] [Full Text] [PDF]
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A. Maitra, D. E. Hansel, P. Argani, R. Ashfaq, A. Rahman, A. Naji, S. Deng, J. Geradts, L. Hawthorne, M. G. House, et al. Global Expression Analysis of Well-Differentiated Pancreatic Endocrine Neoplasms Using Oligonucleotide Microarrays Clin. Cancer Res., December 1, 2003; 9(16): 5988 - 5995. [Abstract] [Full Text] [PDF]
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F. Koga, S. Kawakami, Y. Fujii, K. Saito, Y. Ohtsuka, A. Iwai, N. Ando, T. Takizawa, Y. Kageyama, and K. Kihara Impaired p63 Expression Associates with Poor Prognosis and Uroplakin III Expression in Invasive Urothelial Carcinoma of the Bladder Clin. Cancer Res., November 15, 2003; 9(15): 5501 - 5507. [Abstract] [Full Text] [PDF]
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S. Zha, S. Ferdinandusse, S. Denis, R. J. Wanders, C. M. Ewing, J. Luo, A. M. De Marzo, and W. B. Isaacs {alpha}-Methylacyl-CoA Racemase as an Androgen-Independent Growth Modifier in Prostate Cancer Cancer Res., November 1, 2003; 63(21): 7365 - 7376. [Abstract] [Full Text] [PDF]
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 M. Gariboldi, M. Spinola, S. Milani, C. Pignatiello, K. Kadota, H. Bono, Y. Hayashizaki, T. A. Dragani, and Y. Okazaki Gene expression profile of normal lungs predicts genetic predisposition to lung cancer in mice Carcinogenesis, November 1, 2003; 24(11): 1819 - 1826. [Abstract] [Full Text] [PDF]
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J. A. Mobley, I. Leav, P. Zielie, C. Wotkowitz, J. Evans, Y.-W. Lam, B. S. L'Esperance, Z. Jiang, and S.-M. Ho Branched Fatty Acids in Dairy and Beef Products Markedly Enhance {alpha}-Methylacyl-CoA Racemase Expression in Prostate Cancer Cells in Vitro Cancer Epidemiol. Biomarkers Prev., August 1, 2003; 12(8): 775 - 783. [Abstract] [Full Text] [PDF]
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S. Rossi, E. Graner, P. Febbo, L. Weinstein, N. Bhattacharya, T. Onody, G. Bubley, S. Balk, and M. Loda Fatty Acid Synthase Expression Defines Distinct Molecular Signatures in Prostate Cancer Mol. Cancer Res., August 1, 2003; 1(10): 707 - 715. [Abstract] [Full Text] [PDF]
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G. L. Shen-Ong, Y. Feng, and D. A. Troyer Expression Profiling Identifies a Novel {alpha}-Methylacyl-CoA Racemase Exon with Fumarate Hydratase Homology Cancer Res., June 15, 2003; 63(12): 3296 - 3301. [Abstract] [Full Text] [PDF]
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J. P.T. Higgins, R. Shinghal, H. Gill, J. H. Reese, M. Terris, R. J. Cohen, M. Fero, J. R. Pollack, M. van de Rijn, and J. D. Brooks Gene Expression Patterns in Renal Cell Carcinoma Assessed by Complementary DNA Microarray Am. J. Pathol., March 1, 2003; 162(3): 925 - 932. [Abstract] [Full Text] [PDF]
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V. Srikantan, M. Valladares, J. S. Rhim, J. W. Moul, and S. Srivastava HEPSIN Inhibits Cell Growth/Invasion in Prostate Cancer Cells Cancer Res., December 1, 2002; 62(23): 6812 - 6816. [Abstract] [Full Text] [PDF]
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S. L. Zheng, B.-l. Chang, D. A. Faith, J. R. Johnson, S. D. Isaacs, G. A. Hawkins, A. Turner, K. E. Wiley, E. R. Bleecker, P. C. Walsh, et al. Sequence Variants of {alpha}-Methylacyl-CoA Racemase Are Associated with Prostate Cancer Risk Cancer Res., November 15, 2002; 62(22): 6485 - 6488. [Abstract] [Full Text] [PDF]
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A. Dash, I. P. Maine, S. Varambally, R. Shen, A. M. Chinnaiyan, and M. A. Rubin Changes in Differential Gene Expression because of Warm Ischemia Time of Radical Prostatectomy Specimens Am. J. Pathol., November 1, 2002; 161(5): 1743 - 1748. [Abstract] [Full Text] [PDF]
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R. Kuefer, S. Varambally, M. Zhou, P. C. Lucas, M. Loeffler, H. Wolter, T. Mattfeldt, R. E. Hautmann, J. E. Gschwend, T. R. Barrette, et al. {alpha}-Methylacyl-CoA Racemase: Expression Levels of this Novel Cancer Biomarker Depend on Tumor Differentiation Am. J. Pathol., September 1, 2002; 161(3): 841 - 848. [Abstract] [Full Text] [PDF]
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 Z. Jiang, B. A. Woda, X. J. Yang, M. A. Rubin, and A. M. Chinnaiyan {alpha}-Methylacyl Coenzyme A Racemase as a Marker for Prostate Cancer JAMA, June 19, 2002; 287(23): 3080 - 3081. [Full Text] [PDF]
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